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Hypoxia induced paclitaxel resistance in human ovarian cancers via hypoxia-inducible factor 1α

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Abstracts

Purpose

Chemoresistance severely restricts the anti-cancer medicines from effectively treating human ovarian cancer, which has been shown to develop and survive in the specific hypoxic environments. To understand the relationship between hypoxia and chemoresistance, we investigated the potential role of hypoxia in the pathophysiology of chemoresistance, especially focusing on hypoxia-inducible factor 1α (HIF-1α).

Methods

The A2780 ovarian cancer cells are cultured in gradient hypoxic conditions (5% O2, 3% O2, and 1% O2), the sensitivity of the cells to paclitaxel and the cell inhibitory rate were determined by MTT assay. The expression and the transcriptional activity of HIF-1α were examined by western blot, Immunocytochemical staining, reverse transcription–polymerase chain reaction (RT–PCR), and the dual luciferase reporter system, respectively. The cell cycle distribution was analyzed by flow cytometry. In addition, we silence HIF-1α expression by performing RNA interference.

Results

MTT assay demonstrates that hypoxic challenge substantially reduces the susceptibility of cells to paclitaxel at all the tested concentrations. Coincident with this is the activation of HIF-1α in nuclear, which displays the increased transcriptional activity and high protein expression. Hypoxic manipulation (5% O2, ~1% O2) significantly increased the cell population at G0/G1. Interestingly, knockdown of endogenous HIF-1α significantly alleviates the chemoresistance and promotes G1/S transition with the increased sensitivity of A2780 cells to paclitaxel under each hypoxic condition.

Conclusions

It suggests that HIF-1α, stimulated by hypoxia, exerts a pivotal role in chemoresistance by G0/G1 arrest. Eliminating hypoxic conditions or silencing HIF-1α by siRNA might provide a potent tool to enhance paclitaxel effectiveness in treatment of human ovarian cancer.

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Acknowledgments

This work was supported by National Science Foundation of China (No. 30672227; 30571950), the “973” Program of China (No. 2002CB513100) and the Chenguang Project for Youth of Wuhan City, (No. 200750731294).

Conflict of interest statement

None.

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Authors and Affiliations

  1. Cancer Biology Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave., 430030, Wuhan, Hubei, People’s Republic of China

    Lei Huang, Xiaokui Yang, Hui Xing, Fang Li, Gang Chen, Jianfeng Zhou, Shixuan Wang, Gang Xu, Li Meng, YunPing Lu & Ding Ma

  2. Department of Pathology, Tongji Hospital, Tongji Medical College, 430030, Wuhan, Hubei, People’s Republic of China

    Qilin Ao

  3. Department of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030, Wuhan, Hubei, People’s Republic of China

    Qilin Ao

  4. Key Laboratory of Respiratory Diseases, Ministry of Health (Huazhong University of Science and Technology), 430030, Wuhan, Hubei, People’s Republic of China

    Qilin Ao

  5. Department of Obstetrics and Gynecology, Central Hospital of Wuhan, 430014, Wuhan, Hubei, People’s Republic of China

    Lei Huang & Qinghua Zhang

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  1. Lei Huang
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  2. Qilin Ao
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  3. Qinghua Zhang
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  13. Ding Ma
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Corresponding author

Correspondence to Ding Ma.

Additional information

Lei Huang and Qilin Ao contributed equally to this manuscript.

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Huang, L., Ao, Q., Zhang, Q. et al. Hypoxia induced paclitaxel resistance in human ovarian cancers via hypoxia-inducible factor 1α. J Cancer Res Clin Oncol 136, 447–456 (2010). https://doi.org/10.1007/s00432-009-0675-4

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  • DOI: https://doi.org/10.1007/s00432-009-0675-4

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