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Heat shock proteins and p53 play a critical role in K+ channel-mediated tumor cell proliferation and apoptosis

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Abstract

Plasma membrane potassium (K+) channels are required for tumor cell proliferation and apoptosis. However, the signal transduction mechanisms underlying K+ channel-dependent tumor cell proliferation or apoptosis remains elusive. Using HeLa and A2780 cells as study models, we tested the hypothesis that apoptotic proteins are linked with K+ channel-dependent tumor cell cycle and apoptosis. The patch-clamping study using the whole-cell mode revealed two components of voltage-gated outward K+ currents: one is sensitive to either tetraethylammonium (TEA) or tetrandrine (Tet), a maxi-conductance Ca2+-activated K+ (BK) channel blocker, and the other is sensitive to 4-aminopyridine (4-AP), a delayed rectifier K+ channel blocker. MTT and flow cytometry assays showed that TEA, Tet, or iberiotoxin (Ibtx), a selective BK channel blocker, inhibited HeLa and A2780 cell proliferation in a dose-dependent manner with G1 phase arrest. Pretreatment with TEA or Tet also induced apoptosis in HeLa and A2780 cells. However, glibenclamide (Gli), an ATP-sensitive K+ channel blocker, did not influence K+ currents, proliferation or apoptosis. Western blot analyses showed that while pretreatment of TEA and Tet produced an increase in expressions of p53, p21, and Bax, pretreatment of these two agents led to a decrease in expressions of heat shock protein (hsp)90α, hsp90β, and hsp70. Our results indicate that the blockade of BK channels results in tumor cell apoptosis and cycle arrest at G1 phase, and the transduction pathway underlying the anti-proliferative effects is linked to the increased expression of apoptotic protein p53 and the decreased expression of its chaperone proteins hsp.

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Acknowledgments

This work was supported by grants from the National Science Foundation of China (No. 30571950, 30500596; 30626029; 30672227) and the “973” Program of China (No. 2002CB513100).

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Authors and Affiliations

  1. Cancer Biology Reseach Center, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China

    Xiaobing Han, Hui Xing, Danhui Weng, Xiaohong Song, Gang Chen, Ling Xi, Tao Zhu, Jianfeng Zhou, Gang Xu, Shixuan Wang, Li Meng & Ding Ma

  2. Department of Obstetrics & Gynecology, 1st Hospital, Xi’an Jiaotong University, Xian, Shanxi, 710061, P. R. China

    Xiaobing Han

  3. Department of Pharmacology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China

    Fang Wang & Weixing Yao

  4. Department of Neurology and Neuroscience, Weill Cornell Medical College, New York, NY, 10021, USA

    Costantino Iadecola & Gang Wang

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  1. Xiaobing Han
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  2. Fang Wang
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Correspondence to Gang Wang or Ding Ma.

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Han, X., Wang, F., Yao, W. et al. Heat shock proteins and p53 play a critical role in K+ channel-mediated tumor cell proliferation and apoptosis. Apoptosis 12, 1837–1846 (2007). https://doi.org/10.1007/s10495-007-0101-9

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  • DOI: https://doi.org/10.1007/s10495-007-0101-9

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