RESUMO
Androgen-withdrawal-induced apoptosis (AWIA) is deregulated in androgen refractory prostate cancer. Androgens have been shown to positively regulate expression of the antiapoptotic FADD-like interleukin-1beta-converting enzyme (FLICE)-like inhibitory protein (FLIP), and reduced FLIP expression precedes apoptosis after androgen withdrawal. Here, we show that FLIP protein expression is downregulated in castrated rats, while in LNCaP cells, androgens regulate FLIP in a manner that is dependent on phosphoinositol-3-kinase (PI3K) and Akt signaling. Specifically, treatment of LNCaP cells with LY294002, or expression of either PTEN or a non-phosphorylatable form of FOXO3a (FOXO3aTM), downregulates FLIP protein and mRNA. Conversely, treatment with androgens in the absence of PI3/Akt signaling, or following expression of FOXO3aTM, leads to increased FLIP expression. A FOXO3a binding site was identified in the FLIP promoter and shown necessary for the combined effects of androgens and FOXO3a on FLIP transcription. FOXO3a binds the androgen receptor, suggesting that the transcriptional synergy depends on an interaction between these proteins. Finally, LNCaP cells are sensitized to TRAIL-induced apoptosis by PTEN or LY294002, and rescued by androgens. FOXO3aTM also sensitizes cells to androgen-inhibited TRAIL apoptosis. Androgen rescue was diminished when either FOXO3a or FLIP was reduced by siRNA. These data support a role for FOXO3a in AWIA.
Assuntos
Androgênios/fisiologia , Apoptose/efeitos dos fármacos , Proteína Reguladora de Apoptosis Semelhante a CASP8 e FADD/genética , Fatores de Transcrição Forkhead/fisiologia , Regulação Neoplásica da Expressão Gênica , Neoplasias da Próstata/tratamento farmacológico , Ligante Indutor de Apoptose Relacionado a TNF/farmacologia , Sítios de Ligação , Proteína Reguladora de Apoptosis Semelhante a CASP8 e FADD/análise , Proteína Reguladora de Apoptosis Semelhante a CASP8 e FADD/fisiologia , Linhagem Celular Tumoral , Cromonas/farmacologia , Proteína Forkhead Box O3 , Humanos , Masculino , Morfolinas/farmacologia , PTEN Fosfo-Hidrolase/fisiologia , Fosfatidilinositol 3-Quinases/fisiologia , Inibidores de Fosfoinositídeo-3 Quinase , Regiões Promotoras Genéticas , Próstata/química , Neoplasias da Próstata/química , Neoplasias da Próstata/patologia , Receptores Androgênicos/análise , Receptores Androgênicos/metabolismo , Transdução de SinaisRESUMO
The role of viral infections in the aetiopathogenesis of polymyositis remains speculative. We report a case of profound subacute polymyositis with incipient ventilatory failure following serologically confirmed infection by respiratory syncytial virus (RSV), with a dramatic and sustained response to pulse corticosteroid therapy. We suggest a possible autoimmune mechanism to account for this sequence of events.
