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

Yang,Xiaoyu; Yin,Hubin; Zhang,Yunzhi; Li,Xinyuan; Tong,Hang; Zeng,Yizhou; Wang,Quan; He,Weiyang

doi:10.3892/ijo.2018.4376

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
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Affiliations: Department of Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China, Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China
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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