Lapatinib inhibits CIP2A/PP2A/p-Akt signaling and induces apoptosis in triple negative breast cancer cells
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Chun-Yu Liu1,2, Ming-Hung Hu3,4, Chia-Jung Hsu1, Chun-Teng Huang2,5, Duen-Shian Wang1, Wen-Chun Tsai1, Yi-Ting Chen1, Chia-Han Lee1, Pei-Yi Chu10, Chia-Chi Hsu11, Ming-Huang Chen1,2, Chung-Wai Shiau6, Ling-Ming Tseng2,7 and Kuen-Feng Chen8,9
1 Division of Medical Oncology, Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan
2 School of Medicine, National Yang-Ming University, Taipei, Taiwan
3 Division of Hematology and Oncology, Department of Medicine, Cardinal Tien Hospital, New Taipei City, Taiwan
4 School of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan
5 Division of Hematology & Oncology, Department of Medicine, Yang-Ming Branch of Taipei City Hospital, Taipei, Taiwan
6 Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei, Taiwan
7 Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan
8 Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan
9 National Taiwan University College of Medicine, Taipei, Taiwan
10 Department of Pathology, Show Chwan Memorial Hospital, Changhua City, Taiwan
11 Institute of Pharmacology, National Yang-Ming University, Taipei, Taiwan
Kuen-Feng Chen, email:
Ling-Ming Tseng, email:
Keywords: lapatinib, triple-negative breast cancer, PP2A, CIP2A, apoptosis
Received: July 07, 2015 Accepted: January 19, 2016 Published: January 27, 2016
We tested the efficacy of lapatinib, a dual tyrosine kinase inhibitor which interrupts the HER2 and epidermal growth factor receptor (EGFR) pathways, in a panel of triple-negative breast cancer (TNBC) cells, and examined the drug mechanism. Lapatinib showed an anti-proliferative effect in HCC 1937, MDA-MB-468, and MDA-MB-231 cell lines. Lapatinib induced significant apoptosis and inhibited CIP2A and p-Akt in a dose and time-dependent manner in the three TNBC cell lines. Overexpression of CIP2A reduced lapatinib-induced apoptosis in MDA-MB-468 cells. In addition, lapatinib increased PP2A activity (in relation to CIP2A inhibition). Moreover, lapatinib-induced apoptosis and p-Akt downregulation was attenuated by PP2A antagonist okadaic acid. Furthermore, lapatinib indirectly decreased CIP2A transcription by disturbing the binding of Elk1 to the CIP2A promoter. Importantly, lapatinib showed anti-tumor activity in mice bearing MDA-MB-468 xenograft tumors, and suppressed CIP2A as well as p-Akt in these xenografted tumors. In summary, inhibition of CIP2A determines the effects of lapatinib-induced apoptosis in TNBC cells. In addition to being a dual tyrosine kinase inhibitor of HER2 and EGFR, lapatinib also inhibits CIP2A/PP2A/p-Akt signaling in TNBC cells.
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