SET antagonist enhances the chemosensitivity of non-small cell lung cancer cells by reactivating protein phosphatase 2A
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Man-Hsin Hung3,4,5,6, Cheng-Yi Wang8, Yen-Lin Chen9, Pei-Yi Chu10, Yung-Jen Hsiao1, Wei-Tien Tai1,2, Ting-Ting Chao8, Hui-Chuan Yu1, Chung-Wai Shiau7, Kuen-Feng Chen1,2
1Department of Medical Research, National Taiwan University Hospital, Zhongzheng District, Taiwan
2National Center of Excellence for Clinical Trial and Research, National Taiwan University Hospital, Zhongzheng District, Taiwan
3Division of Medical Oncology, Department of Oncology, Taipei Veterans General Hospital, Taipei City, Taiwan
4Division of Hematology and Oncology, Department of Medicine, Taipei Veterans General Hospital, Taipei City, Taiwan
5Program in Molecular Medicine, School of Life Science, National Yang-Ming University, Taipei City, Taiwan
6School of Medicine, National Yang-Ming University, Taipei City, Taiwan
7Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei City, Taiwan
8Medical Research Center, Cardinal Tien Hospital, Fu Jen Catholic University, New Taipei, Taiwan
9Department of Pathology, Cardinal Tien Hospital, Fu Jen Catholic University, New Taipei, Taiwan
10Department of Pathology, Show Chwan Memorial Hospital, Changhua City, Taiwan
Chung-Wai Shiau, e-mail: [email protected]
Kuen-Feng Chen, e-mail: [email protected]
Keywords: SET, protein phosphatase 2A, non-small cell lung cancer, chemoresistance, Akt
Received: May 20, 2015 Accepted: October 30, 2015 Published: November 13, 2015
SET is known as a potent PP2A inhibitor, however, its oncogenic role including its tumorigenic potential and involvement in the development of chemoresistance in non-small cell lung cancer (NSCLC) has not yet been fully discussed. In present study, we investigated the oncogenic role of SET by SET-knockdown and showed that SET silencing impaired cell growth rate, colony formation and tumor sphere formation in A549 cells. Notably, silencing SET enhanced the pro-apoptotic effects of paclitaxel, while ectopic expression of SET diminished the sensitivity of NSCLC cells to paclitaxel. Since the SET protein was shown to affect chemosensitivity, we next examined whether combining a novel SET antagonist, EMQA, sensitized NSCLC cells to paclitaxel. Both the in vitro and in vivo experiments suggested that EMQA and paclitaxel combination treatment was synergistic. Importantly, we found that downregulating p-Akt by inhibiting SET-mediated protein phosphatase 2A (PP2A) inactivation determined the pro-apoptotic effects of EMQA and paclitaxel combination treatment. To dissect the critical site for EMQA functioning, we generated several truncated SET proteins. By analysis of the effects of EMQA on the binding affinities of different truncated SET proteins to PP2A-catalytic subunits, we revealed that the 227–277 amino-acid sequence is critical for EMQA-induced SET inhibition. Our findings demonstrate the critical role of SET in NSCLC, particularly in the development of chemoresistance. The synergistic effects of paclitaxel and the SET antagonist shown in current study encourage further validation of the clinical potential of this combination.
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