Pirarubicin induces an autophagic cytoprotective response through suppression of the mammalian target of rapamycin signaling pathway in human bladder cancer cells.

Abstract

Pirarubicin is widely used in intravesical chemotherapy for bladder cancer, but its efficacy is limited due to drug resistance; the mechanism has not been well studied. Emerging evidence shows that autophagy can be a novel target for cancer therapy. This study aimed to investigate the role of autophagy in pirarubicin-treated bladder cancer cells. Bladder cancer cells EJ and J82 were treated with pirarubicin, siRNA, 3-methyladenine or hydroxychloroquine. Cell proliferation and apoptosis were tested by cell survival assay and flow cytometric analysis, respectively. Autophagy was evaluated by immunoblotting before and after the treatments. The phosphorylated mammalian target of rapamycin, serine/threonine kinase p70 S6 kinase, and eukaryotic translation initiation factor 4E binding protein 1 were also investigated by immunoblotting. We found that pirarubicin could induce autophagy in bladder cancer cells. Inhibition of autophagy by 3-methyladenine, hydroxychloroquine or knockdown of autophagy related gene 3 significantly increased apoptosis in pirarubicin-treated bladder cancer cells. Pirarubicin-induced autophagy was mediated via the mTOR/p70S6K/4E-BP1 signaling pathway. In conclusion, autophagy induced by pirarubicin plays a cytoprotective role in bladder cancer cells, suggesting that inhibition of autophagy may improve efficacy over traditional pirarubicin chemotherapy in bladder cancer patients.

• Authors: Kuiqing Li, Xu Chen, Cheng Liu, Peng Gu, Zhuohang Li, Shaoxu Wu, Kewei Xu, Tianxin Lin, Jian Huang
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 460 Issue 2 Pg. 380-5 (May 01 2015) ISSN: 1090-2104 [Electronic] United States
• PMID: 25791481 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Inc. All rights reserved.

Chemical References

• Antineoplastic Agents
• Doxorubicin
• pirarubicin
• MTOR protein, human
• TOR Serine-Threonine Kinases

Topics

• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Autophagy (drug effects)
• Doxorubicin (analogs & derivatives, pharmacology)
• Humans
• Signal Transduction (drug effects)
• TOR Serine-Threonine Kinases (metabolism)
• Urinary Bladder Neoplasms (immunology, metabolism, pathology)