Hypoxia-induced autophagy promotes gemcitabine resistance in human bladder cancer cells through hypoxia-inducible factor 1α activation

  • Authors:
    • Xiaoyu Yang
    • Hubin Yin
    • Yunzhi Zhang
    • Xinyuan Li
    • Hang Tong
    • Yizhou Zeng
    • Quan Wang
    • Weiyang He
  • View Affiliations

  • Published online on: April 24, 2018     https://doi.org/10.3892/ijo.2018.4376
  • Pages: 215-224
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Abstract

Overcoming the chemoresistance of bladder cancer is a pivotal obstacle in clinical treatments. Hypoxia widely exists in solid tumors and has been demonstrated to contribute to chemoresistance through hypoxia-inducible factor 1α (HIF‑1α)-mediated autophagy in several types of cancer. However, it is unclear whether HIF‑1α-mediated autophagy and chemoresistance occur in bladder cancer. The present study demonstrated that HIF‑1α was overexpressed in 20 bladder cancer tissues compared with matched paracarcinoma tissues. Gemcitabine-induced apoptosis during hypoxia was significantly reduced compared with that observed under normoxic conditions. In addition, hypoxia activated autophagy and enhanced gemcitabine-induced autophagy. Combined treatment using gemcitabine and an autophagy inhibitor (3-methyladenine) under hypoxia significantly increased gemcitabine cytotoxicity. Furthermore, it was demonstrated that hypoxia-activated autophagy depended on the HIF‑1α/BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3)/Beclin1 signaling pathway. Suppressing HIF‑1α inhibited autophagy, BNIP3 and Beclin1, as well as enhanced gemcitabine-induced apoptosis in bladder cancer cells under hypoxic conditions. Consequently, the results of the present study demonstrated that hypoxia-induced cytoprotective autophagy counteracted gemcitabine-induced apoptosis through increasing HIF‑1α expression. Therefore, targeting HIF‑1α-associated pathways or autophagy in bladder cancer may be a successful strategy to enhance the sensitivity of bladder cancer chemotherapy.
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July 2018
Volume 53 Issue 1

Print ISSN: 1019-6439
Online ISSN:1791-2423

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Copy and paste a formatted citation
APA
Yang, X., Yin, H., Zhang, Y., Li, X., Tong, H., Zeng, Y. ... He, W. (2018). Hypoxia-induced autophagy promotes gemcitabine resistance in human bladder cancer cells through hypoxia-inducible factor 1α activation. International Journal of Oncology, 53, 215-224. https://doi.org/10.3892/ijo.2018.4376
MLA
Yang, X., Yin, H., Zhang, Y., Li, X., Tong, H., Zeng, Y., Wang, Q., He, W."Hypoxia-induced autophagy promotes gemcitabine resistance in human bladder cancer cells through hypoxia-inducible factor 1α activation". International Journal of Oncology 53.1 (2018): 215-224.
Chicago
Yang, X., Yin, H., Zhang, Y., Li, X., Tong, H., Zeng, Y., Wang, Q., He, W."Hypoxia-induced autophagy promotes gemcitabine resistance in human bladder cancer cells through hypoxia-inducible factor 1α activation". International Journal of Oncology 53, no. 1 (2018): 215-224. https://doi.org/10.3892/ijo.2018.4376