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

Research output: Contribution to journalArticlepeer-review

25 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)9135-9149
Number of pages15
JournalOncotarget
Volume7
Issue number8
DOIs
Publication statusPublished - 2016
Externally publishedYes

Keywords

  • Apoptosis
  • CIP2A
  • Lapatinib
  • PP2A
  • Triple-negative breast cancer

ASJC Scopus subject areas

  • Oncology

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