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1.
Mol Carcinog ; 61(10): 958-971, 2022 10.
Article in English | MEDLINE | ID: mdl-35975910

ABSTRACT

Transforming Growth Factor ß1 (TGFß1) is a critical regulator of tumor progression in response to HRas. Recently, TGFß1 has been shown to trigger ER stress in many disease models; however, its role in oncogene-induced ER stress is unclear. Oncogenic HRas induces the unfolded protein response (UPR) predominantly via the Inositol-requiring enzyme 1α (IRE1α) pathway to initiate the adaptative responses to ER stress, with importance for both proliferation and senescence. Here, we show a role of the UPR sensor proteins IRE1α and (PKR)-like endoplasmic reticulum kinase (PERK) to mediate the tumor-suppressive roles of TGFß1 in mouse keratinocytes expressing mutant forms of HRas. TGFß1 suppressed IRE1α phosphorylation and activation by HRas both in in vitro and in vivo models while simultaneously activating the PERK pathway. However, the increase in ER stress indicated an uncoupling of ER stress and IRE1α activation by TGFß1. Pharmacological and genetic approaches demonstrated that TGFß1-dependent dephosphorylation of IRE1α was mediated by PERK through RNA Polymerase II Associated Protein 2 (RPAP2), a PERK-dependent IRE1α phosphatase. In addition, TGFß1-mediated growth arrest in oncogenic HRas keratinocytes was partially dependent on PERK-induced IRE1α dephosphorylation and inactivation. Together, these results demonstrate a critical cross-talk between UPR proteins that is important for TGFß1-mediated tumor suppressive responses.


Subject(s)
Endoribonucleases , RNA Polymerase II , Animals , Endoplasmic Reticulum Stress/genetics , Endoribonucleases/genetics , Endoribonucleases/metabolism , Inositol , Keratinocytes/metabolism , Mice , Protein Serine-Threonine Kinases/genetics , Transforming Growth Factor beta1/genetics , Transforming Growth Factor beta1/metabolism , Unfolded Protein Response , eIF-2 Kinase/metabolism
2.
Mol Carcinog ; 60(5): 342-353, 2021 05.
Article in English | MEDLINE | ID: mdl-33713497

ABSTRACT

The transcription factor Twist1 has been reported to be essential for the formation and invasiveness of chemically induced tumors in mouse skin. However, the impact of keratinocyte-specific Twist1 deletion on skin carcinogenesis caused by UVB radiation has not been reported. Deletion of Twist1 in basal keratinocytes of mouse epidermis using K5.Cre × Twist1flox/flox mice led to significantly reduced UVB-induced epidermal hyperproliferation. In addition, keratinocyte-specific deletion of Twist1 significantly suppressed UVB-induced skin carcinogenesis. Further analyses revealed that deletion of Twist1 in cultured keratinocytes or mouse epidermis in vivo led to keratinocyte differentiation. In this regard, deletion of Twist1 in epidermal keratinocytes showed significant induction of early and late differentiation markers, including TG1, K1, OVOL1, loricrin, and filaggrin. Similar results were obtained with topical application of harmine, a Harmala alkaloid that leads to degradation of Twist1. In contrast, overexpression of Twist1 in cultured keratinocytes suppressed calcium-induced differentiation. Further analyses using both K5.Cre × Twist1flox/flox mice and an inducible system where Twist1 was deleted in bulge region keratinocytes showed loss of expression of hair follicle stem/progenitor markers, including CD34, Lrig1, Lgr5, and Lgr6. These data support the conclusion that Twist1 has a direct role in maintaining the balance between proliferation and differentiation of keratinocytes and keratinocyte stem/progenitor populations. Collectively, these results demonstrate a critical role for Twist1 early in the process of UVB skin carcinogenesis, and that Twist1 may be a novel target for the prevention of cutaneous squamous cell carcinoma.


Subject(s)
Carcinoma, Squamous Cell/genetics , Skin Neoplasms/genetics , Twist-Related Protein 1/genetics , Ultraviolet Rays/adverse effects , Administration, Topical , Animals , Carcinoma, Squamous Cell/drug therapy , Carcinoma, Squamous Cell/etiology , Carcinoma, Squamous Cell/metabolism , Cell Differentiation , Cells, Cultured , Epithelial-Mesenchymal Transition/drug effects , Female , Gene Expression Regulation, Neoplastic/drug effects , Gene Knockout Techniques , Harmine/administration & dosage , Harmine/pharmacology , Keratinocytes/cytology , Keratinocytes/metabolism , Keratinocytes/pathology , Male , Mice , Skin Neoplasms/drug therapy , Skin Neoplasms/etiology , Skin Neoplasms/metabolism
3.
Mol Carcinog ; 58(9): 1656-1669, 2019 09.
Article in English | MEDLINE | ID: mdl-31237385

ABSTRACT

In this study, we evaluated the role of signal transducer and activator of transcription 1 (STAT1) in response to acute solar ultraviolet (SUV) radiation in mouse epidermis. Analysis of the epidermis from SUV-irradiated mice revealed rapid phosphorylation of STAT1 (pSTAT1) on both tyrosine (tyr701) and serine (ser727) residues and increased levels of IRF-1 while later timepoints showed increased levels of unphosphorylated STAT1 (uSTAT1). STAT1 activation led to upregulation of several proinflammatory chemokine mRNAs in epidermis including Cxcl9, Cxcl10, and Ccl2, as well as, the immune checkpoint inhibitor Pd-l1. In addition, mRNA and protein levels of cyclooxygenase-2 (Cox-2/COX2) were upregulated in epidermis following exposure to SUV. Mice with keratinocyte-specific STAT1 deletion did not exhibit increased IRF-1 or proinflammatory gene expression in epidermis. Furthermore, epidermal COX-2 induction after SUV exposure was significantly reduced in mice with keratinocyte-specific deletion of STAT1. Additionally, SUV irradiation rapidly upregulated interferon gamma (IFNγ) mRNA in the epidermis and that skin resident epidermal CD3 + T-cells were the source of IFNγ production. IFNγ receptor-deficient mice confirmed dependency of STAT1 activation, proinflammatory gene expression and COX-2 upregulation in the epidermis on paracrine IFNγ signaling. Furthermore, keratinocyte-specific STAT1-deficiency reduced proliferation and hyperplasia due to SUV irradiation and this was associated with decreased immune infiltration of mast cells in the dermis. Collectively, the current results demonstrate that exposure to SUV leads to upregulation of IFNγ and downstream pSTAT1/IRF-1/uSTAT1 signaling in the epidermis. Further study of this pathway could lead to identification of novel targets for the prevention of nonmelanoma skin cancer.


Subject(s)
Interferon Regulatory Factor-1/metabolism , Interferon-gamma/metabolism , Keratinocytes/metabolism , STAT1 Transcription Factor/metabolism , Signal Transduction/physiology , Ultraviolet Rays/adverse effects , Animals , CD3 Complex/metabolism , Cyclooxygenase 2/metabolism , Epidermal Cells/metabolism , Epidermis/metabolism , Gene Expression/physiology , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Transgenic , RNA, Messenger/metabolism , Skin/metabolism , Skin Neoplasms/metabolism , T-Lymphocytes/metabolism , Up-Regulation/physiology
4.
Toxicol Sci ; 171(1): 146-158, 2019 Sep 01.
Article in English | MEDLINE | ID: mdl-31225620

ABSTRACT

The aryl hydrocarbon receptor (AHR) mediates 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced toxicity that can lead to chloracne in humans. A characteristic of chloracne, in contrast to acne vulgaris, is shrinkage or loss of sebaceous glands. Acne vulgaris, on the other hand, is often accompanied by excessive sebum production. Here, we examined the role of AHR in lipid synthesis in human sebocytes using distinct classes of AHR ligands. Modulation of AHR activity attenuated the expression of lipogenic genes and key proinflammatory markers in the absence of canonical DRE-driven transcription of the AHR target gene CYP1A1. Furthermore, topical treatment with TCDD, which mediates DRE-dependent activity, and SGA360, which fails to induce DRE-mediated responses, both exhibited a decrease in the size of sebaceous glands and the number of sebocytes within each gland in the skin. To elucidate the mechanism of AHR-mediated repression of lipid synthesis, we demonstrated that selective AHR modulators, SGA360 and SGA315 increased the protein turnover of the mature sterol regulatory element-binding protein (mSREBP-1), the principal transcriptional regulator of the fatty acid synthesis pathway. Interestingly, selective AHR ligand treatment significantly activated the AMPK-dependent kinase (AMPK) in sebocytes. Moreover, we demonstrated an inverse correlation between the active AMPK and the mSREBP-1 protein, which is consistent with the previously reported role of AMPK in inhibiting cleavage of SREBP-1. Overall, our findings indicate a DRE-independent function of selective AHR ligands in modulating lipid synthesis in human sebocytes, which might raise the possibility of using AHR as a therapeutic target for treatment of acne.

5.
Mol Carcinog ; 58(9): 1623-1630, 2019 09.
Article in English | MEDLINE | ID: mdl-31041814

ABSTRACT

Cancer is associated with a number of conditions such as hypoxia, nutrient deprivation, cellular redox, and pH changes that result in accumulation of unfolded or misfolded proteins in the endoplasmic reticulum (ER) and trigger a stress response known as the unfolded protein response (UPR). The UPR is a conserved cellular survival mechanism mediated by the ER transmembrane proteins activating transcription factor 6, protein kinase-like endoplasmic reticulum kinase, and inositol-requiring enzyme 1α (IRE1α) that act to resolve ER stress and promote cell survival. IRE1α is a kinase/endoribonuclease (RNase) with multiple activities including unconventional splicing of the messenger RNA (mRNA) for the transcription factor X-Box Binding Protein 1 (XBP1), degradation of other mRNAs in a process called regulated IRE1α-dependent decay (RIDD) and activation of a pathway leading to c-Jun N-terminal kinase phosphorylation. Each of these outputs plays a role in the adaptive and cell death responses to ER stress. Many studies indicate an important role for XBP1 and RIDD functions in cancer and new studies suggest that these two functions of the IRE1α RNase can have opposing functions in the early and later stages of cancer pathogenesis. Finally, as more is learned about the context-dependent role of IRE1α in cancer development, specific small molecule inhibitors and activators of IRE1α could play an important role in counteracting the protective shield provided by ER stress signaling in cancer cells.


Subject(s)
Endoribonucleases/genetics , Gene Expression Regulation/genetics , Neoplasms/genetics , Unfolded Protein Response/genetics , Animals , Endoplasmic Reticulum/genetics , Endoplasmic Reticulum Stress/genetics , Humans , RNA, Messenger/genetics , Signal Transduction/genetics
6.
Proc Natl Acad Sci U S A ; 114(37): 9900-9905, 2017 09 12.
Article in English | MEDLINE | ID: mdl-28847931

ABSTRACT

Oncogenic Ras causes proliferation followed by premature senescence in primary cells, an initial barrier to tumor development. The role of endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) in regulating these two cellular outcomes is poorly understood. During ER stress, the inositol requiring enzyme 1α (IRE1α) endoribonuclease (RNase), a key mediator of the UPR, cleaves Xbp1 mRNA to generate a potent transcription factor adaptive toward ER stress. However, IRE1α also promotes cleavage and degradation of ER-localized mRNAs essential for cell death. Here, we show that oncogenic HRas induces ER stress and activation of IRE1α. Reduction of ER stress or Xbp1 splicing using pharmacological, genetic, and RNAi approaches demonstrates that this adaptive response is critical for HRas-induced proliferation. Paradoxically, reduced ER stress or Xbp1 splicing promotes growth arrest and premature senescence through hyperactivation of the IRE1α RNase. Microarray analysis of IRE1α- and XBP1-depleted cells, validation using RNA cleavage assays, and 5' RACE identified the prooncogenic basic helix-loop-helix transcription factor ID1 as an IRE1α RNase target. Further, we demonstrate that Id1 degradation by IRE1α is essential for HRas-induced premature senescence. Together, our studies point to IRE1α as an important node for posttranscriptional regulation of the early Ras phenotype that is dependent on both oncogenic signaling as well as stress signals imparted by the tumor microenvironment and could be an important mechanism driving escape from Ras-induced senescence.


Subject(s)
Endoplasmic Reticulum Stress/physiology , Endoribonucleases/metabolism , Protein Serine-Threonine Kinases/metabolism , Ribonucleases/metabolism , ras Proteins/genetics , Animals , Apoptosis/physiology , Cell Proliferation/physiology , Endoplasmic Reticulum/metabolism , Endoplasmic Reticulum/physiology , Endoplasmic Reticulum Stress/genetics , Endoribonucleases/genetics , Inositol/metabolism , Keratinocytes/cytology , Keratinocytes/physiology , Mice , Mice, Inbred C57BL , Primary Cell Culture , Protein Serine-Threonine Kinases/genetics , RNA Splicing , RNA Stability , RNA, Messenger/metabolism , Ribonucleases/genetics , Signal Transduction , Transcription Factors/metabolism , Unfolded Protein Response , X-Box Binding Protein 1/genetics , X-Box Binding Protein 1/metabolism , ras Proteins/metabolism
7.
J Biol Chem ; 289(29): 20102-19, 2014 Jul 18.
Article in English | MEDLINE | ID: mdl-24898257

ABSTRACT

Endoplasmic reticulum (ER) stress and ER stress-associated unfolded protein response (UPR) can promote cancer cell survival, but it remains unclear whether they can influence oncogene-induced senescence. The present study examined the role of ER stress in senescence using oncogene-dependent models. Increased ER stress attenuated senescence in part by up-regulating phosphorylated protein kinase B (p-AKT) and decreasing phosphorylated extracellular signal-regulated kinase (p-ERK). A positive feed forward loop between p-AKT, ER stress, and UPR was discovered whereby a transient increase of ER stress caused reduced senescence and promotion of tumorigenesis. Decreased ER stress was further correlated with increased senescence in both mouse and human tumors. Interestingly, H-RAS-expressing Pparß/δ null cells and tumors having increased cell proliferation exhibited enhanced ER stress, decreased cellular senescence, and/or enhanced tumorigenicity. Collectively, these results demonstrate a new role for ER stress and UPR that attenuates H-RAS-induced senescence and suggest that PPARß/δ can repress this oncogene-induced ER stress to promote senescence in accordance with its role as a tumor modifier that suppresses carcinogenesis.


Subject(s)
Cellular Senescence/genetics , Cellular Senescence/physiology , Endoplasmic Reticulum Stress , Genes, ras , PPAR delta/metabolism , PPAR-beta/metabolism , Activating Transcription Factor 4/genetics , Adenoma/genetics , Adenoma/metabolism , Adenoma/pathology , Animals , Cell Transformation, Neoplastic/genetics , Cell Transformation, Neoplastic/metabolism , Cells, Cultured , Colonic Neoplasms/genetics , Colonic Neoplasms/metabolism , Colonic Neoplasms/pathology , DNA-Binding Proteins/genetics , Endoplasmic Reticulum Chaperone BiP , Gene Expression , Gene Knockdown Techniques , Genes, p53 , Heat-Shock Proteins/genetics , Humans , Keratinocytes/cytology , Keratinocytes/metabolism , Mice , Models, Biological , PPAR delta/deficiency , PPAR delta/genetics , PPAR-beta/deficiency , PPAR-beta/genetics , Proto-Oncogene Proteins c-akt/metabolism , RNA, Small Interfering/genetics , Regulatory Factor X Transcription Factors , Signal Transduction , Skin Neoplasms/genetics , Skin Neoplasms/metabolism , Skin Neoplasms/pathology , TOR Serine-Threonine Kinases/metabolism , Transcription Factors/genetics , Unfolded Protein Response
8.
Mol Cell Biol ; 32(11): 2065-82, 2012 Jun.
Article in English | MEDLINE | ID: mdl-22473992

ABSTRACT

The role of peroxisome proliferator-activated receptor ß/δ (PPARß/δ) in Harvey sarcoma ras (Hras)-expressing cells was examined. Ligand activation of PPARß/δ caused a negative selection with respect to cells expressing higher levels of the Hras oncogene by inducing a mitotic block. Mitosis-related genes that are predominantly regulated by E2F were induced to a higher level in HRAS-expressing Pparß/δ-null keratinocytes compared to HRAS-expressing wild-type keratinocytes. Ligand-activated PPARß/δ repressed expression of these genes by direct binding with p130/p107, facilitating nuclear translocation and increasing promoter recruitment of p130/p107. These results demonstrate a novel mechanism of PPARß/δ cross talk with E2F signaling. Since cotreatment with a PPARß/δ ligand and various mitosis inhibitors increases the efficacy of increasing G2/M arrest, targeting PPARß/δ in conjunction with mitosis inhibitors could become a suitable option for development of new multitarget strategies for inhibiting RAS-dependent tumorigenesis.


Subject(s)
E2F4 Transcription Factor/metabolism , G2 Phase Cell Cycle Checkpoints , Mitosis , PPAR delta/metabolism , PPAR-beta/metabolism , Proto-Oncogene Proteins p21(ras)/biosynthesis , Receptor Cross-Talk , Animals , Cells, Cultured , Keratinocytes/metabolism , Mice , Proto-Oncogene Proteins p21(ras)/genetics , Signal Transduction
9.
Mol Cancer Res ; 9(6): 746-56, 2011 Jun.
Article in English | MEDLINE | ID: mdl-21521744

ABSTRACT

TGFß has both tumor suppressive and oncogenic roles in cancer development. We previously showed that SB431542 (SB), a small molecule inhibitor of the TGFß type I receptor (ALK5) kinase, suppressed benign epidermal tumor formation but enhanced malignant conversion. Here, we show that SB treatment of primary K5rTA/tetORASV12G bitransgenic keratinocytes did not alter HRASV12G-induced keratinocyte hyperproliferation. However, continuous SB treatment significantly enhanced HRASV12G-induced cornified envelope formation and cell death linked to increased expression of enzymes transglutaminase (TGM) 1 and TGM3 and constituents of the cornified envelope small proline-rich protein (SPR) 1A and SPR2H. In contrast, TGFß1 suppressed cornified envelope formation in HRASV12G keratinocytes. Similar results were obtained in HRASV12G transgenic mice treated topically with SB or by coexpressing TGFß1 and HRASV12G in the epidermis. Despite significant cell death, SB-resistant HRASV12G keratinocytes repopulated the primary culture that had overcome HRas-induced senescence. These cells expressed reduced levels of p16(ink4a) and were growth stimulated by SB but remained sensitive to a calcium-induced growth arrest. Together these results suggest that differential responsiveness to cornification may represent a mechanism by which pharmacologic blockade of TGFß signaling can inhibit the outgrowth of preneoplastic lesions but may cause a more progressed phenotype in a separate keratinocyte population.


Subject(s)
Keratinocytes/metabolism , Protein Serine-Threonine Kinases/antagonists & inhibitors , Protein Serine-Threonine Kinases/metabolism , Receptors, Transforming Growth Factor beta/antagonists & inhibitors , Receptors, Transforming Growth Factor beta/metabolism , Animals , Benzamides/pharmacology , Cell Differentiation/drug effects , Cell Proliferation , Cells, Cultured , Dioxoles/pharmacology , Genes, ras/genetics , Humans , Keratinocytes/drug effects , Mice , Receptor, Transforming Growth Factor-beta Type I , Signal Transduction/genetics , Transforming Growth Factor beta/metabolism , Transglutaminases/metabolism
10.
J Invest Dermatol ; 130(9): 2295-303, 2010 Sep.
Article in English | MEDLINE | ID: mdl-20410912

ABSTRACT

Overexpression of transforming growth factor-beta1 (TGFbeta1) in the normal epidermis can provoke an inflammatory response, but whether this occurs within a developing tumor is not clear. To test this, we used an inducible transgenic mouse to overexpress TGFbeta1 in premalignant squamous lesions. Within 48 hours of TGFbeta1 induction, there was an increase in IL-17 production by both CD4(+) and gammadelta(+) T cells, together with increased expression of T-helper-17 (Th17)-polarizing cytokines. Induction of TGFbeta1 in premalignant primary keratinocytes elevated the expression of proinflammatory and Th17-polarizing cytokines, and the keratinocyte-conditioned media caused IL-17 production by naive T cells that was dependent on T-cell TGFbeta1 signaling. Microarray analysis showed significant upregulation of proinflammatory genes 2 days after TGFbeta1 induction, and this was followed by increased MPO(+), F4/80(+), and CD8(+) cells in tumors, increased CD8(+) effectors and IFNgamma(+) cells in skin-draining LNs, and tumor regression. In parallel, the percentage of tumor CD11b(+)Ly6G(+) neutrophils was reduced. Neutralization of IL-17 blocked TGFbeta1-induced CD11b(+) Ly6G(-) tumor infiltration but did not alter the reduction of neutrophils or tumor regression. Thus, TGFbeta1 overexpression causes IL-17-dependent and IL-17-independent changes in the premalignant tumor inflammatory microenvironment.


Subject(s)
Carcinoma, Squamous Cell/immunology , Dermatitis/immunology , Interleukin-17 , Precancerous Conditions/immunology , Skin Neoplasms/immunology , Transforming Growth Factor beta1 , Animals , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/metabolism , CD4-Positive T-Lymphocytes/pathology , Carcinoma, Squamous Cell/pathology , Cells, Cultured , Dermatitis/pathology , Disease Progression , Epidermis/immunology , Epidermis/metabolism , Epidermis/pathology , Interleukin-17/genetics , Interleukin-17/immunology , Interleukin-17/metabolism , Keratinocytes/immunology , Keratinocytes/metabolism , Keratinocytes/pathology , Mice , Mice, Transgenic , Oligonucleotide Array Sequence Analysis , Papilloma/immunology , Papilloma/pathology , Precancerous Conditions/pathology , Receptors, Antigen, T-Cell, gamma-delta/metabolism , Signal Transduction/immunology , Skin Neoplasms/pathology , Transforming Growth Factor beta1/genetics , Transforming Growth Factor beta1/immunology , Transforming Growth Factor beta1/metabolism
11.
Mol Carcinog ; 48(5): 441-53, 2009 May.
Article in English | MEDLINE | ID: mdl-18942075

ABSTRACT

Interactions between TGFbeta1 and ras signaling pathways play an important role in cancer development. Here we show that in primary mouse keratinocytes, v-ras(Ha) does not block the early biochemical events of TGFbeta1 signal transduction but does alter global TGFbeta1 mediated gene expression in a gene specific manner. Expression of Smad3 dependent TGFbeta1 early response genes and the TGFbeta1 cytostatic gene expression response were not altered by v-ras(Ha) consistent with an intact TGFbeta1 growth arrest. However, TGFbeta1 and v-ras(Ha) cause significant alteration in genes regulating matrix remodeling as the TGFbeta1 induction of extracellular matrix genes was blocked by v-ras(Ha) but specific matrix proteases associated with cancer progression were elevated. Smad3 deletion in keratinocytes repressed normal differentiation maker expression and caused expression of Keratin 8 a simple epithelial keratin and marker of malignant conversion. Smad3 was required for the TGFbeta1 cytostatic response in v-ras(Ha) keratinocytes, but also for protease induction, keratinocyte attachment and migration. These results show that pro-oncogenic activities of TGFbeta1 can occur early in carcinogenesis before loss of its tumor suppressive function and that selective regulation rather than complete inactivation of Smad3 function may be crucial for tumor progression.


Subject(s)
Genes, Tumor Suppressor , Oncogenes , Skin Neoplasms/genetics , Skin Neoplasms/pathology , Smad3 Protein/physiology , Transforming Growth Factor beta1/physiology , Animals , Cells, Cultured , Culture Media, Conditioned , Keratinocytes/cytology , Mice , Mice, Inbred BALB C , Oligonucleotide Array Sequence Analysis , Signal Transduction , Transcription, Genetic , Transforming Growth Factor beta1/metabolism
12.
Carcinogenesis ; 29(12): 2406-14, 2008 Dec.
Article in English | MEDLINE | ID: mdl-18799709

ABSTRACT

Peroxisome proliferator-activated receptor (PPAR)beta/delta-null mice exhibit enhanced tumorigenesis in a two-stage chemical carcinogenesis model as compared with wild-type mice. Previous work showed that ligand activation of PPARbeta/delta induces terminal differentiation and inhibits proliferation of primary keratinocytes, and this effect does not occur in the absence of PPARbeta/delta expression. In the present studies, the effect of ligand activation of PPARbeta/delta on skin tumorigenesis was examined using both in vivo and ex vivo skin carcinogenesis models. Inhibition of chemically induced skin tumorigenesis was observed in wild-type mice administered GW0742, and this effect was likely the result of ligand-induced terminal differentiation and inhibition of replicative DNA synthesis. These effects were not found in similarly treated PPARbeta/delta-null mice. Ligand activation of PPARbeta/delta also inhibited cell proliferation and induced terminal differentiation in initiated/neoplastic keratinocyte cell lines representing different stages of skin carcinogenesis. These studies suggest that topical administration of PPARbeta/delta ligands may be useful as both a chemopreventive and/or a chemotherapeutic approach to inhibit skin cancer.


Subject(s)
Cell Transformation, Neoplastic/metabolism , PPAR delta/metabolism , PPAR-beta/metabolism , Skin Neoplasms/metabolism , Acetone/toxicity , Animals , Carcinogens/toxicity , Cell Differentiation/drug effects , Cell Differentiation/physiology , Cell Proliferation/drug effects , Enzyme Activation/physiology , Female , Keratinocytes/drug effects , Keratinocytes/metabolism , Keratinocytes/pathology , Ligands , Mice , Mice, Mutant Strains , Skin Neoplasms/chemically induced , Tetradecanoylphorbol Acetate/toxicity , Thiazoles/toxicity
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