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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
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