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1.
Apoptosis ; 26(3-4): 184-194, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33515314

RESUMO

Previously we have shown inhibition of endometrial cancer cell growth with progesterone and calcitriol. However, the mechanisms by which the two agents attenuate proliferation have not been well characterized yet. Herein, we investigated how progesterone and calcitriol induce apoptosis in cancer cells. DNA fragmentation was upregulated by progesterone and calcitriol in ovarian and endometrial cancer cells. Time-dependent treatment of ovarian cancer cells, ES-2, and TOV-21G with progesterone enhanced caspase -8 activity after 12 h, whereas OV-90, TOV-112D, HEC-1A, and HEC-59 cells showed increased activity after 24 h. Caspase 9 activity was increased in all cell lines after 24 h treatment with calcitriol. Pretreatment of cancer cells with a caspase-8 inhibitor (z-IETD-fmk) or caspase-9 inhibitor (Z-LEHD-fmk) significantly attenuated progesterone and calcitriol induced caspase-8 and caspase-9 expression, respectively. The expression of FasL, Fas, FAD, and pro-caspase-8, which constitute the death-inducing signaling complex (DISC), was upregulated in progesterone treated cancer cells. Knockdown of FAS or FADD with specific siRNAs significantly blocked progesterone-induced caspase-8. Cleavage of the BID was not affected by caspase-8 activation suggesting the absence of cross-talk between caspase-8 and caspase-9 pathways. Calcitriol treatment decreased mitochondrial membrane potential and increased the release of cancer cytochrome C. These findings indicate that progesterone induces apoptosis through activation of caspase-8 and calcitriol through caspase-9 activation in cancer cells. A combination of progesterone-calcitriol activates both extrinsic and intrinsic apoptotic pathways in cancer cells.


Assuntos
Apoptose/efeitos dos fármacos , Caspases , Neoplasias do Endométrio/metabolismo , Neoplasias Ovarianas/metabolismo , Progesterona/farmacologia , Calcitriol/metabolismo , Caspase 8/efeitos dos fármacos , Caspase 8/metabolismo , Caspase 9/efeitos dos fármacos , Caspase 9/metabolismo , Caspases/efeitos dos fármacos , Caspases/metabolismo , Linhagem Celular Tumoral , Citocromos c/efeitos dos fármacos , Citocromos c/metabolismo , Proteínas Adaptadoras de Sinalização de Receptores de Domínio de Morte/efeitos dos fármacos , Proteínas Adaptadoras de Sinalização de Receptores de Domínio de Morte/metabolismo , Superfamília de Domínios de Morte/efeitos dos fármacos , Neoplasias do Endométrio/tratamento farmacológico , Proteína Ligante Fas/efeitos dos fármacos , Proteína Ligante Fas/metabolismo , Feminino , Humanos , Técnicas In Vitro , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Neoplasias Ovarianas/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Receptor fas/efeitos dos fármacos , Receptor fas/metabolismo
2.
Cell Biol Int ; 42(10): 1377-1385, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29957841

RESUMO

ß-Elemene, an anti-cancer drug extracted from traditional Chinese medicinal herb, showed anti-tumor effects on gastric cancer cells. Our previous studies reported gastric cancer cells are insensitive to TRAIL. However, whether ß-elemene could enhance anti-cancer effects of TRAIL on gastric cancer cells is unknown. In our present study, ß-elemene prevented gastric cancer cell viability in dose-dependent manner, and when combined with TRAIL, obviously inhibited proliferation and promoted apoptosis in gastric cancer cells. Compared to ß-elemene or TRAIL alone, treatment with ß-elemene and TRAIL obviously promoted DR5 clustering as well as translocation of Caspase-8, DR5 and FADD into lipid rafts. This led to cleavage of Caspase-8 and the formation of death-inducing signaling complex (DISC) in lipid rafts. The cholesterol-sequestering agent nystatin partially reversed DR5 clustering and DISC formation, preventing apoptosis triggered by the combination of ß-elemene and TRAIL. Our results suggest that ß-elemene increases the sensitivity of gastric cancer cells to TRAIL partially by promoting the formation of DISC in lipid rafts.


Assuntos
Sesquiterpenos/metabolismo , Sesquiterpenos/farmacologia , Neoplasias Gástricas/metabolismo , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Caspase 8/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , China , Proteínas Adaptadoras de Sinalização de Receptores de Domínio de Morte/efeitos dos fármacos , Proteínas Adaptadoras de Sinalização de Receptores de Domínio de Morte/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Microdomínios da Membrana , Transdução de Sinais/efeitos dos fármacos , Neoplasias Gástricas/patologia , Ligante Indutor de Apoptose Relacionado a TNF/efeitos dos fármacos , Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Ligante Indutor de Apoptose Relacionado a TNF/farmacologia
3.
Biochim Biophys Acta ; 1863(8): 2104-14, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27208428

RESUMO

Transforming growth factor-beta (TGF-ß) induces the epithelial to mesenchymal transition (EMT) in breast epithelial cells and plays an important role in mammary morphogenesis and breast cancer. In non-transformed breast epithelial cells TGF-ß antagonizes epidermal growth factor (EGF) action and induces growth inhibition. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been reported to participate in lumen formation during morphogenesis of human breast epithelial cells. Our previous work indicated that sensitivity of human breast epithelial cells to TRAIL can be modulated through the activation of the epidermal growth factor receptor-1 (EGFR). Here, we show that TGF-ß opposes EGF-mediated sensitization to TRAIL-induced caspase-8 activation and apoptosis in non-transformed breast epithelial cells. Death-inducing signalling complex (DISC) formation by TRAIL was significantly reduced in cells treated with TGF-ß. TGF-ß treatment activates cytoprotective autophagy and down-regulates TRAIL-R2 expression at the cell surface by promoting the intracellular accumulation of this receptor. Lastly, we demonstrate that EMT is not involved in the inhibitory effect of TGF-ß on apoptosis by TRAIL. Together, the data reveal a fine regulation by EGF and TGF-ß of sensitivity of human breast epithelial cells to TRAIL which may be relevant during morphogenesis.


Assuntos
Apoptose/fisiologia , Mama/citologia , Fator de Crescimento Epidérmico/fisiologia , Células Epiteliais/metabolismo , Ligante Indutor de Apoptose Relacionado a TNF/fisiologia , Fator de Crescimento Transformador beta1/fisiologia , Antígenos CD , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Autofagia/fisiologia , Caderinas/metabolismo , Células Cultivadas , Proteínas Adaptadoras de Sinalização de Receptores de Domínio de Morte/efeitos dos fármacos , Fator de Crescimento Epidérmico/antagonistas & inibidores , Fator de Crescimento Epidérmico/farmacologia , Células Epiteliais/citologia , Transição Epitelial-Mesenquimal/fisiologia , Feminino , Células HeLa , Humanos , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Proteínas Recombinantes/farmacologia , Ligante Indutor de Apoptose Relacionado a TNF/farmacologia , Fator de Crescimento Transformador beta1/farmacologia
4.
Br J Pharmacol ; 169(8): 1723-44, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23638798

RESUMO

UNLABELLED: Anti-tumour therapies based on the use pro-apoptotic receptor agonists, including TNF-related apoptosis-inducing ligand (TRAIL) or monoclonal antibodies targeting TRAIL-R1 or TRAIL-R2, have been disappointing so far, despite clear evidence of clinical activity and lack of adverse events for the vast majority of these compounds, whether combined or not with conventional or targeted anti-cancer therapies. This brief review aims at discussing the possible reasons for the lack of apparent success of these therapeutic approaches and at providing hints in order to rationally design optimal protocols based on our current understanding of TRAIL signalling regulation or resistance for future clinical trials. LINKED ARTICLES: This article is part of a themed section on Emerging Therapeutic Aspects in Oncology. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2013.169.issue-8.


Assuntos
Antineoplásicos/farmacologia , Neoplasias/tratamento farmacológico , Receptores de Morte Celular/efeitos dos fármacos , Ligante Indutor de Apoptose Relacionado a TNF/farmacologia , Animais , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais Humanizados/farmacologia , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/efeitos dos fármacos , Proteínas Adaptadoras de Sinalização de Receptores de Domínio de Morte/efeitos dos fármacos , Proteínas Adaptadoras de Sinalização de Receptores de Domínio de Morte/metabolismo , Humanos , Proteínas Recombinantes , Ligante Indutor de Apoptose Relacionado a TNF/efeitos dos fármacos , Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Ligante Indutor de Apoptose Relacionado a TNF/uso terapêutico
5.
BMC Cancer ; 11: 39, 2011 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-21272366

RESUMO

BACKGROUND: rhTRAIL is a therapeutic agent, derived from the TRAIL cytokine, which induces apoptosis in cancer cells by activating the membrane death receptors 4 and 5 (DR4 and DR5). Here, we investigated each receptor's contribution to rhTRAIL sensitivity and rhTRAIL resistance. We assessed whether agonistic DR4 or DR5 antibodies could be used to circumvent rhTRAIL resistance, alone or in combination with various chemotherapies. METHODS: Our study was performed in an isogenic model comprised of the SW948 human colon carcinoma cell line and its rhTRAIL resistant sub-line SW948-TR. Effects of rhTRAIL and agonistic DR4/DR5 antibodies on cell viability were measured using MTT assays and identification of morphological changes characteristic of apoptosis, after acridine orange staining. Sensitivity to the different death receptor ligands was stimulated using pretreatment with the cytokine IFN-gamma and the proteasome inhibitor MG-132. To investigate the mechanisms underlying the changes in rhTRAIL sensitivity, alterations in expression levels of targets of interest were measured by Western blot analysis. Co-immunoprecipitation was used to determine the composition of the death-inducing signalling complex at the cell membrane. RESULTS: SW948 cells were sensitive to all three of the DR-targeting agents tested, although the agonistic DR5 antibody induced only weak caspase 8 cleavage and limited apoptosis. Surprisingly, agonistic DR4 and DR5 antibodies induced equivalent DISC formation and caspase 8 cleavage at the level of their individual receptors, suggesting impairment of further caspase 8 processing upon DR5 stimulation. SW948-TR cells were cross-resistant to all DR-targeting agents as a result of decreased caspase 8 expression levels. Caspase 8 protein expression was restored by MG-132 and IFN-gamma pretreatment, which also re-established sensitivity to rhTRAIL and agonistic DR4 antibody in SW948-TR. Surprisingly, MG-132 but not IFN-gamma could also increase DR5-mediated apoptosis in SW948-TR. CONCLUSIONS: These results highlight a critical difference between DR4- and DR5-mediated apoptotic signaling modulation, with possible implications for future combinatorial regimens.


Assuntos
Carcinoma/patologia , Neoplasias do Colo/patologia , Resistencia a Medicamentos Antineoplásicos , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/fisiologia , Ligante Indutor de Apoptose Relacionado a TNF/uso terapêutico , Anticorpos Monoclonais/farmacologia , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Carcinoma/tratamento farmacológico , Carcinoma/metabolismo , Linhagem Celular Tumoral , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/metabolismo , Proteínas Adaptadoras de Sinalização de Receptores de Domínio de Morte/efeitos dos fármacos , Proteínas Adaptadoras de Sinalização de Receptores de Domínio de Morte/metabolismo , Avaliação Pré-Clínica de Medicamentos , Resistencia a Medicamentos Antineoplásicos/fisiologia , Inibidores Enzimáticos/farmacologia , Humanos , Leupeptinas/farmacologia , Inibidores de Proteassoma , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/agonistas , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/imunologia , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia
6.
Apoptosis ; 13(8): 983-92, 2008 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-18543108

RESUMO

FADD/MORT1 (The adaptor protein of Fas Associate Death Domain/Mediator of Receptor Induced Toxicity) is essential for signal transduction of death receptor signaling. We have previously shown that FADD is significantly up-regulated in TNFalpha/ActD induced apoptosis. Over-expression of FADD also induces death of lung cancer cells and primary hepatocytes. We hypothesize that the increase in detectable FADD levels require the proximal steps in apoptotic signaling and speculated that FADD would be redistributed in cells destined to undergo apoptosis. We show that monomeric non-phosphorylated FADD is up-regulated in hepatocytes treated with TNFalpha/ActD and that it accumulates in the cytoplasm. Nuclear phosphorylated FADD decreases with TNFalpha/ActD treatment. Dimeric FADD in the cytoplasm remains constant with TNFalpha/ActD. The change in FADD levels and distribution was dependent on caspase-3, caspase-8 activity and the presence of BID. Thus, changes in FADD levels and distribution are downstream of caspase activation and mitochondria changes that are initiated by the formation of the DISC complex. Changes in FADD levels and distribution may represent a novel feed-forward mechanism to propagate apoptosis signaling in hepatocytes.


Assuntos
Apoptose/fisiologia , Proteína Agonista de Morte Celular de Domínio Interatuante com BH3/metabolismo , Caspases/metabolismo , Proteína de Domínio de Morte Associada a Fas/metabolismo , Hepatócitos/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Transporte Ativo do Núcleo Celular/efeitos dos fármacos , Transporte Ativo do Núcleo Celular/fisiologia , Animais , Apoptose/efeitos dos fármacos , Proteína Agonista de Morte Celular de Domínio Interatuante com BH3/efeitos dos fármacos , Caspase 3/efeitos dos fármacos , Caspase 3/metabolismo , Caspase 8/efeitos dos fármacos , Caspase 8/metabolismo , Caspases/efeitos dos fármacos , Citoplasma/efeitos dos fármacos , Citoplasma/metabolismo , Dactinomicina/farmacologia , Proteínas Adaptadoras de Sinalização de Receptores de Domínio de Morte/efeitos dos fármacos , Proteínas Adaptadoras de Sinalização de Receptores de Domínio de Morte/metabolismo , Proteína de Domínio de Morte Associada a Fas/efeitos dos fármacos , Hepatócitos/efeitos dos fármacos , Humanos , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Potencial da Membrana Mitocondrial/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fosforilação/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Fator de Necrose Tumoral alfa/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/fisiologia
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