RESUMO
Currently, chemoresistance is an important cause of treatment failure in colorectal cancer. Cancer stem cells, which are a population of multi-potent cells with the capacity to self-renew and differentiate, have been found to participate in chemoresistance. In the present study, the chemotherapeutic drug oxaliplatin induced autophagy in colorectal cancer cell lines, which in turn protected cancer cells from apoptosis. Further results showed that oxaliplatin-induced autophagy enriched the population of colorectal CSCs and participated in maintaining the stemness of colorectal CSCs, thus making the cells more resistant to chemotherapy. Taken together, the results indicate that autophagy might enhance the chemoresistance of colorectal cancer cells by protecting the stemness and chemoresistance of colorectal CSCs. Our study demonstrates that autophagy plays a pro-survival role in colorectal CSCs subjected to oxaliplatin. Therefore, targeting autophagy may be considered as a potential therapeutic strategy to address chemoresistance in the treatment of colorectal cancer.
Assuntos
Antineoplásicos/farmacologia , Autofagia/efeitos dos fármacos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/patologia , Compostos Organoplatínicos/farmacologia , Apoptose/efeitos dos fármacos , Biomarcadores Tumorais/metabolismo , Western Blotting , Proliferação de Células/efeitos dos fármacos , Neoplasias Colorretais/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Citometria de Fluxo , Imunofluorescência , Humanos , Oxaliplatina , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células Tumorais CultivadasRESUMO
Autophagy favors cell survival under hypoxia, and increasing evidence revealed that microRNAs regulate autophagy. We report here hypoxia increased the expression of miR-96 in prostate cancer cells, and miR-96 stimulated autophagy by suppressing MTOR. We found that inhibition of miR-96 abolished hypoxia-induced autophagy. Paradoxically, ectopic over-expression of miR-96 to a certain threshold, also abolished the hypoxia-induced autophagy. Further studies have shown that high levels of miR-96 inhibited autophagy through suppressing ATG7, a key autophagy-associated gene. Importantly, the miR-96 expression level threshold was determined, and the effects of miR-96 on autophagy on either side of the threshold were opposite. These data demonstrate hypoxia-induced autophagy is at least partially regulated by miR-96; miR-96 can promote or inhibit autophagy by principally inhibiting MTOR or ATG7 depending on the expression levels of miR-96. Our observation might reveal a novel regulatory mode of autophagy by microRNAs under hypoxia.