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2.
Cancer Prev Res (Phila) ; 9(10): 794-802, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27388747

RESUMO

Patients with basal cell nevus syndrome (BCNS), also known as Gorlin syndrome, develop numerous basal cell carcinomas (BCC) due to germline mutations in the tumor suppressor PTCH1 and aberrant activation of Hedgehog (Hh) signaling. Therapies targeted at components of the Hh pathway, including the smoothened (SMO) inhibitor vismodegib, can ablate these tumors clinically, but tumors recur upon drug discontinuation. Using SKH1-Ptch1+/- as a model that closely mimics the spontaneous and accelerated growth pattern of BCCs in patients with BCNS, we show that AKT1, a serine/threonine protein kinase, is intrinsically activated in keratinocytes derived from the skin of newborn Ptch1+/- mice in the absence of carcinogenic stimuli. Introducing Akt1 haplodeficiency in Ptch1+/- mice (Akt1+/- Ptch1+/-) significantly abrogated BCC growth. Similarly, pharmacological inhibition of AKT with perifosine, an alkyl phospholipid AKT inhibitor, diminished the growth of spontaneous and UV-induced BCCs. Our data demonstrate an obligatory role for AKT1 in BCC growth, and targeting AKT may help reduce BCC tumor burden in BCNS patients. Cancer Prev Res; 9(10); 794-802. ©2016 AACR.


Assuntos
Síndrome do Nevo Basocelular/patologia , Carcinoma Basocelular/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Neoplasias Cutâneas/patologia , Animais , Síndrome do Nevo Basocelular/metabolismo , Carcinoma Basocelular/metabolismo , Linhagem Celular , Modelos Animais de Doenças , Humanos , Queratinócitos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neoplasias Cutâneas/metabolismo
3.
Oncotarget ; 6(34): 36789-814, 2015 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-26413810

RESUMO

Nevoid basal cell carcinoma syndrome (NBCCS) is a rare autosomal dominant disorder that is due, in large measure, to aberrant Shh signaling driven by mutations in the tumor suppressor gene Ptch1. Here, we describe the development of Ptch1+/-/ SKH-1 mice as a novel model of this disease. These animals manifest many features of NBCCS, including developmental anomalies and are remarkably sensitive to both ultraviolet (UVB) and ionizing radiation that drive the development of multiple BCCs. Just as in patients with NBCCS, Ptch1+/-/SKH-1 also spontaneously develops BCCs and other neoplasms such as rhabdomyomas/rhabdomyosarcomas. Administration of smoothened inhibitors (vismodegib/itraconazole/cyclopamine) or non-steroidal anti-inflammatory drug (sulindac/sulfasalazine) each result in partial resolution of BCCs in these animals. However, combined administration of these agents inhibits the growth of UVB-induced BCCs by >90%. Employing small molecule- and decoy-peptide-based approaches we further affirm that complete remission of BCCs could only be achieved by combined inhibition of p50-NFκB/Bcl3 and Shh signaling. We posit that Ptch1+/-/SKH-1 mice are a novel and relevant animal model for NBCCS. Understanding mechanisms that govern genetic predisposition to BCCs should facilitate our ability to identify and treat NBCCS gene carriers, including those at risk for sporadic BCCs while accelerating development of novel therapeutic modalities for these patients.


Assuntos
Síndrome do Nevo Basocelular/metabolismo , Proteínas Hedgehog/metabolismo , Subunidade p50 de NF-kappa B/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Neoplasias Cutâneas/metabolismo , Fatores de Transcrição/metabolismo , Animais , Proteína 3 do Linfoma de Células B , Síndrome do Nevo Basocelular/genética , Síndrome do Nevo Basocelular/patologia , Modelos Animais de Doenças , Feminino , Proteínas Hedgehog/genética , Humanos , Masculino , Camundongos , Camundongos Pelados , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Subunidade p50 de NF-kappa B/genética , Proteínas Proto-Oncogênicas/genética , Transdução de Sinais , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Fatores de Transcrição/genética
4.
PLoS One ; 9(5): e97245, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24824222

RESUMO

p38 mitogen-activated protein kinases (MAPKs) respond to a wide range of extracellular stimuli. While the inhibition of p38 signaling is implicated in the impaired capacity to repair ultraviolet (UV)-induced DNA damage-a primary risk factor for human skin cancers-its mechanism of action in skin carcinogenesis remains unclear, as both anti-proliferative and survival functions have been previously described. In this study, we utilized cultured keratinocytes, murine tumorigenesis models, and human cutaneous squamous cell carcinoma (SCC) specimens to assess the effect of p38 in this regard. UV irradiation of normal human keratinocytes increased the expression of all four p38 isoforms (α/ß/γ/δ); whereas irradiation of p53-deficient A431 keratinocytes derived from a human SCC selectively decreased p38α, without affecting other isoforms. p38α levels are decreased in the majority of human cutaneous SCCs assessed by tissue microarray, suggesting a tumor-suppressive effect of p38α in SCC pathogenesis. Genetic and pharmacological inhibition of p38α and in A431 cells increased cell proliferation, which was in turn associated with increases in NAPDH oxidase (NOX2) activity as well as intracellular reactive oxygen species (ROS). These changes led to enhanced invasiveness of A431 cells as assessed by the matrigel invasion assay. Chronic treatment of p53-/-/SKH-1 mice with the p38 inhibitor SB203580 accelerated UV-induced SCC carcinogenesis and increased the expression of NOX2. NOX2 knockdown suppressed the augmented growth of A431 xenografts treated with SB203580. These findings indicate that in the absence of p53, p38α deficiency drives SCC growth and progression that is associated with enhanced NOX2 expression and ROS formation.


Assuntos
Carcinoma de Células Escamosas/metabolismo , Regulação Enzimológica da Expressão Gênica/efeitos da radiação , Sistema de Sinalização das MAP Quinases/fisiologia , Espécies Reativas de Oxigênio/metabolismo , Neoplasias Cutâneas/metabolismo , Raios Ultravioleta , Animais , Carcinogênese/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células , Células Cultivadas , Humanos , Imidazóis/efeitos adversos , Queratinócitos/metabolismo , Queratinócitos/efeitos da radiação , Sistema de Sinalização das MAP Quinases/efeitos da radiação , Glicoproteínas de Membrana/metabolismo , Camundongos , Camundongos Knockout , Análise em Microsséries , NADPH Oxidase 2 , NADPH Oxidases/metabolismo , Piridinas/efeitos adversos , Proteína Supressora de Tumor p53/deficiência
5.
Am J Pathol ; 184(5): 1529-40, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24631180

RESUMO

Hairless mice carrying homozygous mutations in hairless gene manifest rudimentary hair follicles (HFs), epidermal cysts, hairless phenotype, and enhanced susceptibility to squamous cell carcinomas. However, their susceptibility to basal cell carcinomas (BCCs), a neoplasm considered originated from HF-localized stem cells, is unknown. To demonstrate the role of HFs in BCC development, we bred Ptch(+/-)/C57BL6 with SKH-1 hairless mice, followed by brother-sister cross to get F2 homozygous mutant (hairless) or wild-type (haired) mice. UVB-induced inflammation was less pronounced in shaved haired than in hairless mice. In hairless mice, inflammatory infiltrate was found around the rudimentary HFs and epidermal cysts. Expression of epidermal IL1f6, S100a8, vitamin D receptor, repetin, and major histocompatibility complex II, biomarkers depicting susceptibility to cutaneous inflammation, was also higher. In these animals, HF disruption altered susceptibility to UVB-induced BCCs. Tumor onset in hairless mice was 10 weeks earlier than in haired littermates. The incidence of BCCs was significantly higher in hairless than in haired animals; however, the magnitude of sonic hedgehog signaling did not differ significantly. Overall, 100% of hairless mice developed >12 tumors per mouse after 32 weeks of UVB therapy, whereas haired mice developed fewer than three tumors per mouse after 44 weeks of long-term UVB irradiation. Tumors in hairless mice were more aggressive than in haired littermates and manifested decreased E-cadherin and enhanced mesenchymal proteins. These data provide novel evidence that disruption of HFs in Ptch(+/-) mice enhances cutaneous susceptibility to inflammation and BCCs.


Assuntos
Carcinoma Basocelular/etiologia , Folículo Piloso/patologia , Inflamação/patologia , Neoplasias Induzidas por Radiação/patologia , Receptores de Superfície Celular/metabolismo , Neoplasias Cutâneas/etiologia , Pele/patologia , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Apoptose/efeitos da radiação , Biomarcadores Tumorais/metabolismo , Carcinogênese/efeitos dos fármacos , Carcinogênese/patologia , Carcinogênese/efeitos da radiação , Carcinoma Basocelular/genética , Carcinoma Basocelular/patologia , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/efeitos da radiação , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos da radiação , Folículo Piloso/efeitos dos fármacos , Folículo Piloso/efeitos da radiação , Proteínas Hedgehog/metabolismo , Inflamação/genética , Masculino , Mesoderma/efeitos dos fármacos , Mesoderma/metabolismo , Mesoderma/patologia , Mesoderma/efeitos da radiação , Camundongos Pelados , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Neoplasias Induzidas por Radiação/genética , Receptores Patched , Receptor Patched-1 , Fenótipo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Transdução de Sinais/efeitos da radiação , Pele/efeitos dos fármacos , Pele/efeitos da radiação , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Sulfassalazina/farmacologia , Raios Ultravioleta
6.
PLoS One ; 7(6): e39691, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22761871

RESUMO

In order to model squamous cell carcinoma development in vivo, researchers have long preferred hairless mouse models such as SKH-1 mice that have traditionally been classified as 'wild-type' mice irrespective of the genetic factors underlying their hairless phenotype. The work presented here shows that mutations in the Hairless (Hr) gene not only result in the hairless phenotype of the SKH-1 and Hr(-/-) mouse lines but also cause aberrant activation of NFκB and its downstream effectors. We show that in the epidermis, Hr is an early UVB response gene that regulates NFκB activation and thereby controls cellular responses to irradiation. Therefore, when Hr expression is decreased in Hr mutant animals there is a corresponding increase in NFκB activity that is augmented by UVB irradiation. This constitutive activation of NFκB in the Hr mutant epidermis leads to the stimulation a large variety of downstream effectors including the cell cycle regulators cyclin D1 and cyclin E, the anti-apoptosis protein Bcl-2, and the pro-inflammatory protein Cox-2. Therefore, Hr loss results in a state of uncontrolled epidermal proliferation that promotes tumor development, and Hr mutant mice should no longer be considered merely hairless 'wild-type' mice. Instead, Hr is a crucial UVB response gene and its loss creates a permissive environment that potentiates increased tumorigenesis.


Assuntos
Transformação Celular Neoplásica/genética , NF-kappa B/metabolismo , Transdução de Sinais , Fatores de Transcrição/fisiologia , Raios Ultravioleta , Animais , Camundongos , Camundongos Mutantes , Neoplasias Induzidas por Radiação/genética , Fatores de Transcrição/genética , Regulação para Cima
7.
Biochim Biophys Acta ; 1807(6): 609-19, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21167810

RESUMO

Cancer cells utilize complex mechanisms to remodel their bioenergetic properties. We exploited the intrinsic genomic stability of xeroderma pigmentosum C (XPC) to understand the inter-relationships between genomic instability, reactive oxygen species (ROS) generation, and metabolic alterations during neoplastic transformation. We showed that knockdown of XPC (XPC(KD)) in normal human keratinocytes results in metabolism remodeling through NADPH oxidase-1 (NOX-1) activation, which in turn leads to increased ROS levels. While enforcing antioxidant defenses by overexpressing catalase, CuZnSOD, or MnSOD could not block the metabolism remodeling, impaired NOX-1 activation abrogates both alteration in ROS levels and modifications of energy metabolism. As NOX-1 activation is observed in human squamous cell carcinomas (SCCs), the blockade of NOX-1 could be a target for the prevention and the treatment of skin cancers.


Assuntos
Proteínas de Ligação a DNA/antagonistas & inibidores , Proteínas de Ligação a DNA/genética , Queratinócitos/metabolismo , NADPH Oxidases/metabolismo , Interferência de RNA , Espécies Reativas de Oxigênio/efeitos adversos , Antioxidantes/metabolismo , Sequência de Bases , Células Cultivadas , Proteínas de Ligação a DNA/metabolismo , Ativação Enzimática/efeitos dos fármacos , Ativação Enzimática/fisiologia , Humanos , Queratinócitos/efeitos dos fármacos , Queratinócitos/fisiologia , Redes e Vias Metabólicas/efeitos dos fármacos , Redes e Vias Metabólicas/genética , Modelos Biológicos , Dados de Sequência Molecular , NADPH Oxidase 1 , NADPH Oxidases/fisiologia , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/genética , Estresse Oxidativo/fisiologia , Interferência de RNA/efeitos dos fármacos , Interferência de RNA/fisiologia , RNA Interferente Pequeno/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Homologia de Sequência do Ácido Nucleico
8.
Cancer Prev Res (Phila) ; 3(1): 25-34, 2010 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-20051370

RESUMO

In vitro and epidemiologic studies favor the efficacy of nonsteroidal anti-inflammatory drugs (NSAID) in preventing skin squamous photocarcinogenesis, but there has been relatively little study of their efficacy in preventing the more common skin basal cell carcinoma (BCC) carcinogenesis. We first compared the relative anti-BCC effects of genetic deletion and NSAID pharmacologic inhibition of cyclooxygenase (COX) enzymes in the skin of Ptch1(+/-) mice. We then assessed the effects of celecoxib on the development of BCCs in a 3-year, double-blinded, randomized clinical trial in 60 (PTCH1(+/-)) patients with the basal cell nevus syndrome. In Ptch1(+/-) mice, genetic deletion of COX1 or COX2 robustly decreased (75%; P < 0.05) microscopic BCC tumor burden, but pharmacologic inhibition with celecoxib reduced microscopic BCCs less efficaciously (35%; P < 0.05). In the human trial, we detected a trend for oral celecoxib reducing BCC burden in all subjects (P = 0.069). Considering only the 60% of patients with less severe disease (<15 BCCs at study entry), celecoxib significantly reduced BCC number and burden: subjects receiving placebo had a 50% increase in BCC burden per year, whereas subjects in the celecoxib group had a 20% increase (P(difference) = 0.024). Oral celecoxib treatment inhibited BCC carcinogenesis in PTCH1(+/-) mice and had a significant anti-BCC effect in humans with less severe disease.


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Carcinoma Basocelular/prevenção & controle , Predisposição Genética para Doença , Pirazóis/uso terapêutico , Receptores de Superfície Celular/genética , Neoplasias Cutâneas/prevenção & controle , Sulfonamidas/uso terapêutico , Animais , Síndrome do Nevo Basocelular/complicações , Síndrome do Nevo Basocelular/tratamento farmacológico , Síndrome do Nevo Basocelular/genética , Carcinoma Basocelular/genética , Celecoxib , Quimioprevenção , Ciclo-Oxigenase 1/genética , Ciclo-Oxigenase 2/genética , Método Duplo-Cego , Heterozigoto , Humanos , Camundongos , Camundongos Mutantes , Receptores Patched , Receptor Patched-1 , Neoplasias Cutâneas/genética
9.
Photochem Photobiol ; 84(2): 522-7, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18266822

RESUMO

Cyclooxygenase-2 (COX-2) inhibition can inhibit UVB-induced carcinogenesis in the skin. We have shown that COX-2 is overexpressed in UVB-induced squamous cell carcinomas (SCCs). Celecoxib, a specific inhibitor of COX-2, blocks UVB-induced papillomas and carcinomas in murine skin. However, as COX-2 inhibitors of this type are associated with an increased risk of adverse cardiovascular events, we decided to study nimesulide, a different class of COX-2 inhibitor, an N-arylmethanesulfonamide derivative not known to have these untoward effects. To assess the antitumor-promoting effects of nimesulide, 90 mice were equally divided into three groups. Group I animals received no test agent or UVB and served as age-matched controls; group II animals were irradiated with UVB (180 mJ cm(-2), twice weekly for 35 weeks) and group III animals received 300 p.p.m. nimesulide in drinking water and were irradiated with UVB as described for group-II. Nimesulide treatment reduced the growth of UVB-induced tumors both in terms of tumor number and tumor volume. By weeks 25, 30 and 35, the tumor numbers in the nimesulide-treated group were 79%, 49% and 53% less than the number occurring in UVB-treated animals whereas tumor volume was reduced 69%, 54% and 53%, respectively, compared to the UVB-irradiated control group. Nimesulide also inhibited the malignant progression of SCCs. The reduction in tumorigenesis was paralleled by a decrease in cell cycle regulatory proteins (cyclins A, B1, D1, E, CDK2/4/6) and the antiapoptotic protein (Bcl2); concomitantly there was an increase in proapoptotic markers, poly (ADP-ribose) polymerase (PARP) and caspase-3. Nimesulide also decreased ornithine decarboxylase expression and the nuclear accumulation of nuclear factor kappa B transcriptionally active protein complexes. These results show that alternative classes of COX-2 inhibitors may likely be efficacious as cancer chemopreventive agents and may have an improved therapeutic index.


Assuntos
Ciclo-Oxigenase 2/efeitos dos fármacos , Inibidores de Ciclo-Oxigenase/farmacologia , Neoplasias Induzidas por Radiação/prevenção & controle , Neoplasias Cutâneas/prevenção & controle , Sulfonamidas/farmacologia , Raios Ultravioleta , Animais , Feminino , Camundongos , Camundongos Pelados
10.
J Clin Invest ; 117(12): 3753-64, 2007 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-18060030

RESUMO

Mutations in the tumor suppressor p53 are detectable in over 50% of all human malignancies. Mutant p53 protein is incapable of transactivating its downstream target genes that are required for DNA repair and apoptosis. Chronic exposure to UVB induces p53 mutations and is carcinogenic in both murine and human skin. CP-31398, a styrylquinazoline compound, restores the tumor suppressor functions of mutant forms of p53 in tumor cells. However, its effectiveness in vivo remains unclear. Here, we demonstrate that CP-31398 blocked UVB-induced skin carcinogenesis and was associated with increases in p53, p21, and BclXs. CP-31398 downregulated Bcl2, proliferating nuclear cell antigen, and cyclin D1. Activation of caspase-3 and cleavage of poly (ADP-ribose) polymerase also occurred in both tumor and perilesional skin following treatment. CP-31398 induced the expression of p53-dependent target proteins, and this was followed by apoptosis in UVB-irradiated wild-type mice but not in their p53-deficient littermates. Similar effects were observed in human skin carcinoma A431 cells expressing mutant p53. In addition, CP-31398 induced mitochondrial translocation of p53, leading to changes in mitochondrial membrane permeability pore transition (MPT) and consequent cytochrome c release in these cells. Blocking MPT diminished p53 translocation and apoptosis. These studies indicate that reconstituting p53 tumor suppressor functions in vivo by small molecular weight compounds may block the pathogenesis and progression of skin cancer.


Assuntos
Transformação Celular Neoplásica/efeitos dos fármacos , Exposição Ambiental/efeitos adversos , Mutação/efeitos da radiação , Neoplasias Induzidas por Radiação/tratamento farmacológico , Pirimidinas/farmacologia , Neoplasias Cutâneas/tratamento farmacológico , Proteína Supressora de Tumor p53/metabolismo , Raios Ultravioleta/efeitos adversos , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Apoptose/efeitos da radiação , Caspase 3/genética , Caspase 3/metabolismo , Linhagem Celular Tumoral , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Transformação Celular Neoplásica/efeitos da radiação , Ciclina D , Ciclinas/genética , Ciclinas/metabolismo , Citocromos c/genética , Citocromos c/metabolismo , Feminino , Humanos , Masculino , Camundongos , Camundongos Pelados , Mitocôndrias/genética , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Proteínas de Transporte da Membrana Mitocondrial/antagonistas & inibidores , Proteínas de Transporte da Membrana Mitocondrial/genética , Proteínas de Transporte da Membrana Mitocondrial/metabolismo , Poro de Transição de Permeabilidade Mitocondrial , Mutação/efeitos dos fármacos , Neoplasias Induzidas por Radiação/genética , Neoplasias Induzidas por Radiação/metabolismo , Neoplasias Induzidas por Radiação/patologia , Poli(ADP-Ribose) Polimerases/genética , Poli(ADP-Ribose) Polimerases/metabolismo , Antígeno Nuclear de Célula em Proliferação/genética , Antígeno Nuclear de Célula em Proliferação/metabolismo , Transporte Proteico/efeitos dos fármacos , Transporte Proteico/genética , Transporte Proteico/efeitos da radiação , Pirimidinas/uso terapêutico , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/metabolismo , Proteína Supressora de Tumor p53/genética , Proteína bcl-X/genética , Proteína bcl-X/metabolismo
11.
Toxicol Appl Pharmacol ; 224(3): 274-83, 2007 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-17306316

RESUMO

The search for novel and effective cancer chemopreventive agents has led to the identification of various naturally occurring compounds one of which is resveratrol (trans-3,4',5-trihydroxystilbene), a phytoalexin derived from the skin of grapes and other fruits. Resveratrol is known to have potent anti-inflammatory and antioxidant effects and to inhibit platelet aggregation and the growth of a variety of cancer cells. Its potential chemopreventive and chemotherapeutic activities have been demonstrated in all three stages of carcinogenesis (initiation, promotion, and progression), in both chemically and UVB-induced skin carcinogenesis in mice, as well as in various murine models of human cancers. Evidence from numerous in vitro and in vivo studies has confirmed its ability to modulate various targets and signaling pathways. This review discusses the current preclinical and mechanistic data available and assesses resveratrol's anticancer effects to support its potential as an anticancer agent in human populations.


Assuntos
Anticarcinógenos/farmacologia , Neoplasias/prevenção & controle , Estilbenos/farmacologia , Animais , Anticarcinógenos/uso terapêutico , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Humanos , Neoplasias/patologia , Resveratrol , Estilbenos/uso terapêutico
12.
Exp Dermatol ; 15(9): 667-77, 2006 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-16881963

RESUMO

Basal cell carcinoma (BCC) is the most common human malignancy, affecting 750,000 Americans each year. The understanding of mutations that are known to activate hedgehog (Hh) signalling pathway genes, including PATCHED (PTCH), sonic hedgehog (Shh) and smoothened (Smo), has substantially expanded our current understanding of the genetic basis of BCC development. The Hh signalling pathway is one of the most fundamental signal transduction pathways in embryonic development. In skin, the Shh pathway is crucial for maintaining stem cell population, and for regulating hair follicle and sebaceous gland development. This pathway plays a minimal role in adult tissues, but is known to be activated in many neoplasms, including those arising in the skin. In this review, we attempt to summarize the results of published studies on some important aspects of the Shh pathway and its involvement in skin development and carcinogenesis. We also provide a description of various animal models that have been developed, based on our knowledge of the Shh pathway in human skin cancers. Additionally, we include a brief description of studies conducted in our laboratory and by others on the chemoprevention of BCCs. This review therefore provides a current understanding of the role of the Shh pathway in skin development and neoplasia. It also provides a basis for the molecular target-based chemoprevention and therapeutic management of skin cancer.


Assuntos
Carcinoma Basocelular/fisiopatologia , Transdução de Sinais/fisiologia , Neoplasias Cutâneas/fisiopatologia , Pele/crescimento & desenvolvimento , Transativadores/fisiologia , Animais , Carcinoma Basocelular/etiologia , Carcinoma Basocelular/prevenção & controle , Quimioprevenção , Proteínas Hedgehog , Humanos , Neoplasias Cutâneas/etiologia , Neoplasias Cutâneas/prevenção & controle , Transativadores/genética
13.
J Invest Dermatol ; 124(6): 1318-25, 2005 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-15955110

RESUMO

The p38 mitogen-activated protein kinase (MAPK) signaling pathway is activated by numerous inflammatory mediators and environmental stresses. We assessed the effects of ultraviolet B (UVB) on the p38 MAPK pathway and determined whether cyclooxygenase (COX)-2 expression is downstream of this kinase in the skin of UVB-irradiated SKH-1 mice. SKH-1 mice were irradiated with a single dose of UVB (360 mJ per cm2), and activation of the epidermal p38 MAPK pathway was assessed. UVB-induced phosphorylation of p38 MAPK occurred in a time-dependent manner. Phosphorylation of MAPK-activated protein kinase-2 (MAPKAPK-2) also was detected and correlated with an increase in its kinase activity. Phosphorylation of heat shock protein 27 (HSP27), a substrate for MAPKAPK-2, also was detected post-irradiation. Oral administration of the p38 inhibitor, SB242235, prior to UVB irradiation, blocked activation of the p38 MAPK cascade, and abolished MAPKAPK-2 kinase activity and phosphorylation of HSP27. Moreover, SB242235 inhibited expression of the pro-inflammatory cytokines interleukin (IL)-6 and KC (murine IL-8) and COX-2. Our data demonstrate that UVB irradiation of murine skin activates epidermal p38 MAPK signaling and induces a local pro-inflammatory response. Blockade of the p38 MAPK pathway may offer an effective approach to reducing or preventing skin damage resulting from acute solar radiation.


Assuntos
Transtornos de Fotossensibilidade/etiologia , Raios Ultravioleta , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Animais , Ciclo-Oxigenase 2 , Citocinas/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Feminino , Proteínas de Choque Térmico HSP27 , Proteínas de Choque Térmico/metabolismo , Imidazóis/farmacologia , Mediadores da Inflamação/antagonistas & inibidores , Peptídeos e Proteínas de Sinalização Intracelular , Camundongos , Camundongos Pelados , Fosforilação/efeitos dos fármacos , Fosforilação/efeitos da radiação , Transtornos de Fotossensibilidade/metabolismo , Transtornos de Fotossensibilidade/patologia , Prostaglandina-Endoperóxido Sintases/metabolismo , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Piridinas/farmacologia , Transdução de Sinais/efeitos da radiação , Pele/enzimologia , Pele/metabolismo , Pele/patologia , Pele/efeitos da radiação , Treonina , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores
14.
Cancer Res ; 65(8): 3236-42, 2005 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-15833855

RESUMO

Arsenic is an important environmental carcinogen that affects millions of people worldwide through contaminated water supplies. For decades, arsenic was considered a nongenotoxic carcinogen. Using the highly sensitive A(L) mutation assay, we previously showed that arsenic is, indeed, a potent gene and chromosomal mutagen and that its effects are mediated through the induction of reactive oxygen species. However, the origin of these radicals and the pathways involved are not known. Here we show that mitochondrial damage plays a crucial role in arsenic mutagenicity. Treatment of enucleated cells with arsenic followed by rescue fusion with karyoplasts from controls resulted in significant mutant induction. In contrast, treatment of mitochondrial DNA-depleted (rho(0)) cells produced few or no mutations. Mitochondrial damage can lead to the release of superoxide anions, which then react with nitric oxide to produce the highly reactive peroxynitrites. The mutagenic damage was dampened by the nitric oxide synthase inhibitor, N(G)-methyl-L-arginine. These data illustrate that mitochondria are a primary target in arsenic-induced genotoxic response and that a better understanding of the mutagenic/carcinogenic mechanism of arsenic should provide a basis for better interventional approach in both treatment and prevention of arsenic-induced cancer.


Assuntos
Arsenitos/toxicidade , Mitocôndrias/efeitos dos fármacos , Compostos de Sódio/toxicidade , Tirosina/análogos & derivados , Animais , Células CHO , Cricetinae , Dano ao DNA , DNA Mitocondrial/efeitos dos fármacos , DNA Mitocondrial/genética , Humanos , Células Híbridas , Membranas Intracelulares/efeitos dos fármacos , Membranas Intracelulares/fisiologia , Potenciais da Membrana/efeitos dos fármacos , Mitocôndrias/genética , Mitocôndrias/metabolismo , Mitocôndrias/fisiologia , Testes de Mutagenicidade , Ácido Peroxinitroso/metabolismo , Proteínas/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Tirosina/metabolismo
15.
Cancer Res ; 64(20): 7545-52, 2004 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-15492281

RESUMO

Abnormal activation of the hedgehog-signaling pathway is the pivotal abnormality driving the growth of basal cell carcinomas (BCCs), the most common type of human cancer. Antagonists of this pathway such as cyclopamine may therefore be useful for treatment of basal cell carcinomas and other hedgehog-driven tumors. We report here that chronic oral administration of cyclopamine dramatically reduces ( approximately 66%) UVB induced basal cell carcinoma formation in Ptch1(+/-) mice. Fas expression is low in human and murine basal cell carcinomas but is up-regulated in the presence of the smoothened (SMO) antagonist, cyclopamine, both in vitro in the mouse basal cell carcinoma cell line ASZ001 and in vivo after acute treatment of mice with basal cell carcinomas. This parallels an elevated rate of apoptosis. Conversely, expression of activated SMO in C3H10T1/2 cells inhibits Fas expression. Fas/Fas ligand interactions are necessary for cyclopamine-mediated apoptosis in these cells, a process involving caspase-8 activation. Our data provide strong evidence that cyclopamine and perhaps other SMO antagonists are potent in vivo inhibitors of UVB-induced basal cell carcinomas in Ptch1(+/-) mice and likely in humans because the majority of human basal cell carcinomas manifest mutations in PTCH1 and that a major mechanism of their inhibitory effect is through up-regulation of Fas, which augments apoptosis.


Assuntos
Carcinoma Basocelular/prevenção & controle , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Neoplasias Cutâneas/prevenção & controle , Alcaloides de Veratrum/farmacologia , Receptor fas/biossíntese , Animais , Apoptose/efeitos dos fármacos , Carcinoma Basocelular/etiologia , Carcinoma Basocelular/metabolismo , Carcinoma Basocelular/patologia , Linhagem Celular Tumoral , Proteína Ligante Fas , Peptídeos e Proteínas de Sinalização Intracelular , Glicoproteínas de Membrana/metabolismo , Proteínas de Membrana , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Receptores Patched , Receptor Patched-1 , Proteínas/genética , Receptores de Superfície Celular , Receptores Acoplados a Proteínas G/fisiologia , Transdução de Sinais/efeitos dos fármacos , Neoplasias Cutâneas/etiologia , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Receptor Smoothened , Raios Ultravioleta/efeitos adversos , Receptor fas/metabolismo
16.
J Clin Invest ; 113(6): 867-75, 2004 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-15067319

RESUMO

Solar ultraviolet B (UVB) radiation induces cutaneous ornithine decarboxylase (ODC), the first enzyme in the polyamine-biosynthesis pathway, which drives continued proliferation and clonal expansion of initiated (mutated) cells, leading to tumorigenesis. Therefore ODC is a potentially important target for chemoprevention of basal cell carcinomas (BCCs), the majority of which have mutations in the tumor-suppressor gene known as patched (PTCH). To assess this possibility, we first overexpressed ODC in the skin of Ptch1+/- mice using a keratin 6 (K6) promoter that directs constitutive ODC expression in the outer root sheath of the hair follicle. UVB irradiation of these mice accelerated induction of BCCs as compared with their Ptch1+/- littermates. To further verify the role of ODC in BCC tumorigenesis, we used an antizyme (AZ) approach to inhibit ODC activity in the Ptch1+/- mice. Ptch1+/- mice with AZ overexpression driven by the K6 promoter were resistant to the induction of BCCs by UVB. Furthermore, oral administration of the suicidal ODC inhibitor alpha-difluoromethylornithine reduced UVB-induced BCCs in Ptch1+/- mice. These results demonstrate the crucial importance of ODC for the induction of BCCs and indicate that chemopreventive strategies directed at inhibiting this enzyme may be useful in reducing BCCs in human populations.


Assuntos
Carcinoma Basocelular/prevenção & controle , Carcinoma de Células Escamosas/prevenção & controle , Proteínas de Membrana/genética , Ornitina Descarboxilase/metabolismo , Animais , Carcinoma Basocelular/metabolismo , Carcinoma de Células Escamosas/metabolismo , Eflornitina/farmacologia , Heterozigoto , Peptídeos e Proteínas de Sinalização Intracelular , Proteínas de Membrana/metabolismo , Camundongos , Inibidores da Ornitina Descarboxilase , Receptores Patched , Receptor Patched-1 , Receptores de Superfície Celular , Raios Ultravioleta
17.
Toxicol Appl Pharmacol ; 195(3): 370-8, 2004 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-15020200

RESUMO

Sulindac is a nonsteroidal anti-inflammatory drug with demonstrated potency as a chemopreventive agent in animal models of carcinogenesis and in patients with familial adenomatous polyposis. Because tumor promotion is generally associated with exposure to pro-inflammatory stimuli, it is likely that anti-inflammatory agents may have potent antitumor effects. In human skin, sulindac reduces bradykinin-induced edema. In this study, we tested the hypothesis that the cyclooxygenase inhibitor sulindac can protect against ultraviolet (UVB)-induced injury that is crucial for the induction of cancer. Exposure of SKH-1 hairless mice to two consecutive doses of UVB (230 mJ/cm2) induces various inflammatory responses including erythema, edema, epidermal hyperplasia, infiltration of polymorphonuclear leukocytes, etc. Topical application of sulindac (1.25-5.0 mg/0.2 ml acetone) to the dorsal skin of SKH-1 hairless mice either 1 h before or immediately after UVB exposure substantially inhibited these inflammatory responses in a dose-dependent manner. Oral administration of sulindac in drinking water (160 ppm) for 15 days before and during UVB irradiation similarly reduced these inflammatory responses. These potent anti-inflammatory effects of sulindac suggested the possibility that the drug could inhibit signaling processes that relate to carcinogenic insult by UVB. Accordingly, studies were conducted to assess the efficacy of sulindac in attenuating the expression of UVB-induced early surrogate molecular markers of photodamage and carcinogenesis. UVB exposure enhanced the expression of p53, c-fos, cyclins D1 and A, and PCNA 24 h after irradiation. Treatment of animals with either topical or oral administration of sulindac largely abrogated the expression of these UVB-induced surrogate markers. These results indicate that the cyclooxygenase inhibitor sulindac is effective in reducing UVB-induced events relevant to carcinogenesis and that this category of topically applied or orally administered drugs may prove to be effective chemopreventive agents for reducing the risk of photocarcinogenesis in human populations.


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Dermatite Fototóxica/prevenção & controle , Pele/efeitos da radiação , Sulindaco/uso terapêutico , Raios Ultravioleta/efeitos adversos , Administração Cutânea , Administração Oral , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Ciclinas/biossíntese , Dermatite Fototóxica/etiologia , Dermatite Fototóxica/metabolismo , Dermatite Fototóxica/patologia , Dinoprostona/biossíntese , Relação Dose-Resposta a Droga , Feminino , Camundongos , Camundongos Pelados , Pele/efeitos dos fármacos , Pele/metabolismo , Pele/patologia , Sulindaco/administração & dosagem , Fatores de Tempo , Proteína Supressora de Tumor p53/biossíntese
18.
Photochem Photobiol ; 76(1): 73-80, 2002 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-12126310

RESUMO

Inflammatory stimuli result in the production of cutaneous eicosanoids, which are known to contribute to the process of tumor promotion. Cyclooxygenase (COX), the rate-limiting enzyme for the production of prostaglandins (PG) from arachidonic acid, exists in at least two isoforms, COX-1 and COX-2. COX-1 is constitutively expressed in most tissues and plays various physiological roles, whereas increased COX-2 expression is known to occur in several types of epithelial neoplasms. Enhanced PG synthesis is a potential contributing factor in UVB-induced nonmelanoma skin cancers (NMSC). Increased COX-2 staining occurs in murine skin neoplasms after chronic exposure to carcinogenic doses of UVB. In this study, immunohistochemical and Western blot analyses were employed to assess longitudinally COX-2 expression in a standard mouse UVB complete carcinogenesis protocol and in human basal cell carcinomas (BCC) and squamous cell carcinomas (SCC). During UVB irradiation of mice, COX-2 expression consistently increased in the hyperplastic skin, the benign papillomas and the SCC. COX-2 expression was also increased in human actinic keratoses, SCC and BCC as well as in murine SCC and BCC. The pattern of COX-2 expression was quite variable, occurring in a patchy distribution in some lesions with staining confined mainly to suprabasal cell layers. In general, COX-2 expression progressively became more extensive in benign papillomas and well-differentiated murine SCC. The staining was predominantly cytoplasmic and perinuclear in some focal areas in tissue stroma around both murine and human tumors. Western blot analysis confirmed negative COX-2 expression in normal skin, whereas acute UVB exposure resulted in increased enzyme expression, which continued to increase in developing papillomas and SCC. Because of the evidence indicating a pathogenic role for eicosanoids in murine and human skin neoplasms, we performed studies to assess the anti-inflammatory and anticarcinogenic effects of green tea extracts, which are potent antioxidants. Acute exposure of the human skin to UVB (minimum erythema dose x 4) caused a transient enhancement of the COX-2 expression, which reverted to baseline within hours; however, in murine skin the expression persisted for several days. Pretreatment with the topically applied green tea extract (1 mg/cm2) largely abrogated the acute COX-2 response to UVB in mice or humans. In summary, enhanced COX-2 expression serves as a marker of epidermal UVB exposure for murine and human NMSC. These results suggest that COX-2 inhibitors could have potent anticarcinogenic effects in UVB-induced skin cancer.


Assuntos
Isoenzimas/metabolismo , Prostaglandina-Endoperóxido Sintases/metabolismo , Neoplasias Cutâneas/enzimologia , Adulto , Animais , Ciclo-Oxigenase 2 , Inibidores de Ciclo-Oxigenase 2 , Inibidores de Ciclo-Oxigenase/uso terapêutico , Feminino , Humanos , Masculino , Proteínas de Membrana , Camundongos , Camundongos Pelados , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Camundongos Mutantes , Pessoa de Meia-Idade , Neoplasias Induzidas por Radiação/tratamento farmacológico , Neoplasias Induzidas por Radiação/enzimologia , Pele/enzimologia , Pele/efeitos da radiação , Neoplasias Cutâneas/tratamento farmacológico , Raios Ultravioleta/efeitos adversos
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