Lapatinib inhibits CIP2A/PP2A/p-Akt signaling and induces apoptosis in triple negative breast cancer cells

Chun Yu Liu, Ming Hung Hu, Chia Jung Hsu, Chun Teng Huang, Duen Shian Wang, Wen Chun Tsai, Yi Ting Chen, Chia Han Lee, Pei Yi Chu, Chia Chi Hsu, Ming Huang Chen, Chung Wai Shiau, Ling Ming Tseng, Kuen Feng Chen

研究成果: 雜誌貢獻文章同行評審

45 引文 斯高帕斯(Scopus)

摘要

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.

原文英語
頁(從 - 到)9135-9149
頁數15
期刊Oncotarget
7
發行號8
DOIs
出版狀態已發佈 - 2016
對外發佈

ASJC Scopus subject areas

  • 腫瘤科

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