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

Oncotarget
Chun-Yu LiuKuen-Feng Chen

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 s...Continue Reading

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Citations

Oct 26, 2018·Journal of Cellular and Molecular Medicine·Jing DuanGuang-Biao Zhou
Oct 19, 2020·Journal of Controlled Release : Official Journal of the Controlled Release Society·Jiang NiLiang Han
Aug 27, 2021·Veterinary Sciences·Andreia GameiroFernando Ferreira
Nov 6, 2021·Advanced Healthcare Materials·Shindu C ThomasNalinikanth Kotagiri

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Methods Mentioned

BETA
flow cytometry
transfection
PCR
immunoprecipitation
immunoprecipitation assay
xenograft
xenografts
ChIP

Software Mentioned

SPSS

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