Details

Autor(en) / Beteiligte

• Ojha, Rani
• Jha, V.
• Singh, S.K.

Titel

Gemcitabine and mitomycin induced autophagy regulates cancer stem cell pool in urothelial carcinoma cells

Ist Teil von

• Biochimica et biophysica acta, 2016-02, Vol.1863 (2), p.347-359

Ort / Verlag

Netherlands: Elsevier B.V

Erscheinungsjahr

2016

Link zum Volltext

Quelle

Free E-Journal (出版社公開部分のみ）

Beschreibungen/Notizen

• 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. [Display omitted] •Gemcitabine and mitomycin increased the proportion of cancer stem cells (CSCs) in urothelial carcinoma.•Gemcitabine and mitomycin induced autophagic flux in both CSCs and bulk population.•Increased autophagic flux is critical for bioenergetic demands and maintenance of cancer cell viability.•Inhibition of autophagy decreased the proportion of CSCs and glycolytic gene expression.•Inhibition of both autophagy and glycolysis reduced the expression of stem cell marker and drug resistant genes.