Activation of fibronectin/PI-3K/Akt2 leads to chemoresistance to docetaxel by regulating survivin protein expression in ovarian and breast cancer cells |
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Authors: | Xing Hui Weng Danhui Chen Gang Tao Wenming Zhu Tao Yang Xiaokui Meng Li Wang Shixuan Lu Yunping Ma Ding |
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Affiliation: | Cancer Biology Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, PR China. |
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Abstract: | The purpose of this study was to investigate the possible role of PI-3K/Akt2 pathway in docetaxel-induced apoptosis. Here we showed that transfection of full-length Akt2 into breast and ovarian cancer cells could provoke Akt phosphorylation and induce an enhanced resistance to docetaxel. FN adhesion promoted Akt phosphorylation in highly metastatic cancer cells A2780 and MDAMB231, and further brought on significant protection for tumor cells against docetaxel-induced apoptosis. Inhibition of Akt2 activity by co-transfection with two shRNA vectors targeting the same Akt2 mRNA or simply by administration with PI 3-Kinase inhibitor Ly294002 counteracted the ability of FN to protect cells from undergoing apoptosis induced by docetaxel. We further showed that Akt2 activation protected against docetaxel-induced apoptosis by regulating survivin levels in a PI 3-Kinase-dependent manner. We conclude that FN/PI-3K/Akt2 pathway might play an important role in inducing resistance to docetaxel in breast and ovarian cancer cells. Our results therefore indicate that the activation of Akt2, promoted by FN attachment, might be critical in determining whether cells survive or undergo apoptosis. Targeting the PI-3K/Akt2 pathway might be a promising strategy for enhancing sensitivity to docetaxel in breast or ovarian cancer. |
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Keywords: | Fibronectin Akt2 shRNA Drug resistance Apoptosis Co-transfection |
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