CIP2A is a target of bortezomib in human triple negative breast cancer cellsReportar como inadecuado




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Breast Cancer Research

, 14:R68

First Online: 26 April 2012Received: 12 August 2011Revised: 16 April 2012Accepted: 26 April 2012

Abstract

IntroductionTriple negative breast cancer TNBC is very aggressive and currently has no specific therapeutic targets, such as hormone receptors or human epidermal growth factor receptor type 2 HER2; therefore, prognosis is poor. Bortezomib, a proteasome inhibitor, may exert efficacy in TNBC through its multiple cellular effects. Here, we tested the efficacy of bortezomib and examined the drug mechanism in breast cancer cells.

MethodsFive breast cancer cell lines: TNBC HCC-1937, MDA-MB-231, and MDA-MB-468; HER2-overexpressing MDA-MB-453; and estrogen receptor positive MCF-7 were used for in vitro studies. Apoptosis was examined by both flow cytometry and Western Blot. Signal transduction pathways in cells were assessed by Western Blot. Gene silencing was done by small interfering RNA siRNA. In vivo efficacy of bortezomib was tested in nude mice with breast cancer xenografts. Immunohistochemical study was performed on tumor tissues from patients with TNBC.

ResultsBortezomib induced significant apoptosis, which was independent of its proteasome inhibition, in the three TNBC cell lines, but not in MDA-MB-453 or MCF-7 cells. Furthermore, cancerous inhibitor of protein phosphatase 2A CIP2A, a cellular inhibitor of protein phosphatase 2A PP2A, mediated the apoptotic effect of bortezomib. We showed that bortezomib inhibited CIP2A in association with p-Akt downregulation in a dose- and time-dependent manner in all sensitive TNBC cells, whereas no alterations in CIP2A expression and p-Akt were noted in bortezomib-resistant cells. Overexpression of CIP2A upregulated p-Akt and protected MDA-MB-231 and MDA-MB-468 cells from bortezomib-induced apoptosis, whereas silencing CIP2A by siRNA overcame the resistance to bortezomib-induced apoptosis in MCF-7 cells. In addition, bortezomib downregulated CIP2A mRNA but did not affect the degradation of CIP2A protein. Furthermore, bortezomib exerted in vivo antitumor activity in HCC-1937 xenografted tumors, but not in MCF-7 tumors. Bortezomib downregulated CIP2A expression in the HCC-1937 tumors but not in the MCF-7 tumors. Importantly, CIP2A expression is readily detectable in tumor samples from TNBC patients.

ConclusionsCIP2A is a major determinant mediating bortezomib-induced apoptosis in TNBC cells. CIP2A may thus be a potential therapeutic target in TNBC.

AbbreviationsCIP2Acancerous inhibitor of PP2A

DMEMDulbecco-s modified Eagle-s medium

DMSOdimethyl sulfoxide

ERestrogen receptor

FBSfetal bovine serum

HCChepatocellular carcinoma

HER2human epidermal growth factor receptor type 2

I-κBinhibitor of NF-κB

IHCimmunohistochemical

i.p.intraperitoneal

MBCmetastatic breast cancers

NF-κBnuclear factor-κB

PARPpoly ADP-ribose polymerase

PBSphosphate-buffered saline

PgRprogesterone receptor

PI3Kphosphatidylinositol-3-kinase

PP2Aprotein phosphatase 2A

PTENphosphatase and tensin homologue deleted on chromosome ten

RT-PCRreverse transcriptase polymerase chain reaction

s.c.subcutaneous

siRNAsmall interfering RNA

TNBCtriple negative breast cancer

Electronic supplementary materialThe online version of this article doi:10.1186-bcr3175 contains supplementary material, which is available to authorized users.

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Autor: Ling-Ming Tseng - Chun-Yu Liu - Kung-Chi Chang - Pei-Yi Chu - Chung-Wai Shiau - Kuen-Feng Chen

Fuente: https://link.springer.com/article/10.1186/bcr3175







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