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Fibronectin-mediated activation of Akt2 protects human ovarian and breast cancer cells from docetaxel-induced apoptosis via inhibition of the p38 pathway

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Abstract

Although multiple mechanisms have been implicated in chemoresistance, recent evidence has suggested that the attachment of cells to extracellular matrix proteins such as fibronectin (FN) may mediate the signals that participate in cell survival and resistance to apoptosis. We established previously that human ovarian cancer cells and breast cancer cells adhering to FN acquire a survival advantage through activation of the PI3-kinase/Akt2 pathway. However, the mechanism by which Akt2 regulates chemoresistance in adherent cells is unknown. In the present study, we have investigated the role of the interaction between the Akt2/survivin survivial pathway and the ASK1/p38 apoptotic pathway in the phenomenon of resistance to docetaxel. We show here that the resistance of FN-adhered A2780 or MDA-MB-231 cells to docetaxel requires survivin, and we present evidence that attenuation of the antiapoptotic activity of survivin is p38-dependent. The activation of p38 kinase in response to docetaxel, on the other hand, is abolished by FN adhesion. We further demonstrate that FN adhesion-mediated inhibition of p38 activation was governed by Akt2 via the promotion of direct protein association of ASK1 with p38. Our results indicate for the first time that p38 plays a critical role in FN adhesion-mediated resistance to docetaxel. The present findings may help us to understand the formation of FN adhesion-mediated chemoresistance and facilitate development of novel antineoplastic strategies.

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Abbreviations

ECM:

Extracellular matrix

CAM-DR:

Adhesion-mediated drug resistance

FN:

Fibronectin

PLL:

Polylysine

PI 3K:

Phosphatidyl inositol 3′-kinase

IAP:

Inhibitor of apoptosis

ASK1:

Apoptosis signal-regulating kinase 1

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Acknowledgments

This work was supported by grants from the National Science Foundation of China (No. 30571950, 30371657) and the “973” Program of China (No. 2002 CB513100).

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Authors and Affiliations

  1. Cancer Biology Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, P.R. China

    Hui Xing, Yang Cao, Danhui Weng, Xiaohong Song, Wei Wang, Li Meng, Gang Xu, Jianfeng Zhou, Shixuan Wang & Ding Ma

  2. Department of Obsterics and Gynecology, Xiangfan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Xiangfan, Hubei, 441021, P.R. China

    Hui Xing

  3. Department of Orthepeadecs, Xiangfan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Xiangfan, Hubei, 441021, P.R. China

    Wenming Tao

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  1. Hui Xing
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Correspondence to Shixuan Wang or Ding Ma.

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Note: Hui Xing and yang Chao contributed equally to this work.

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Xing, H., Cao, Y., Weng, D. et al. Fibronectin-mediated activation of Akt2 protects human ovarian and breast cancer cells from docetaxel-induced apoptosis via inhibition of the p38 pathway. Apoptosis 13, 213–223 (2008). https://doi.org/10.1007/s10495-007-0158-5

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