Abstract
Urothelial carcinoma (UC) is characterized by therapeutic resistance and frequent tumor relapse. It has been suggested that UC are driven by a rare subset of cancer stem cells (CSCs). In order to understand UC recurrence post therapy, we investigated the behavior of urothelial CSCs after exposure to commonly used chemotherapeutic agents, gemcitabine (GC) and mitomycin (MM). Although, the role of autophagy in CSC maintenance is well documented, the relationship of autophagy and CSCs with respect to drug resistance remains elusive. In the present study, we found that both GC and MM increased the percentage of CSCs in primary cultured urothelial carcinoma cells (UCC). These CSCs exhibited higher autophagy flux and higher expression of glycolytic genes. Inhibition of autophagy led to decrease in the expression of glycolysis genes. Inhibition of autophagy and glycolysis caused decrease in expression of stemness genes (Oct-4, Nanog), drug resistance genes (ABCG2, MDR1) and sensitized CSCs to GC and MM induced apoptosis. This finding suggests that autophagy and glycolysis may play a central role in drug resistance. Altogether, we conclude that autophagy may support cell survival by buffering bioenergetic demands for maintenance of high glycolytic flux in CSCs. Therefore, autophagy-based, “customized” combinatorial approaches may provide a new method to counter CSC-driven resistance and may prevent relapse in UC.The synergistic cytotoxic effect of GC/ MM with autophagy inhibitor (chloroquine) or with glycolytic inhibitor (2-deoxyglucose) may be of help in improving the outcome in patients with urothelial carcinoma of urinary bladder.
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
More From: Biochimica et Biophysica Acta (BBA) - Molecular Cell Research
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.