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Simvastatin induces derepression of PTEN expression via NFkappaB to inhibit breast cancer cell growth.

Abstract：

:Sustained activation of Akt kinase acts as a focal regulator to increase cell growth and survival, which causes tumorigenesis including breast cancer. Statins, potent inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase, display anticancer activity. The molecular mechanisms by which statins block cancer cell growth are poorly understood. We demonstrate that in the tumors derived from MDA-MB-231 human breast cancer cell xenografts, simvastatin significantly inhibited phosphorylation of Akt with concomitant attenuation of the expression of the anti-apoptotic protein Bcl(XL). In many cancer cells, Bcl(XL) is a target of NFkappaB. Simvastatin inhibited the DNA binding and transcriptional activities of NFkappaB resulting in marked reduction in transcription of Bcl(XL). Signals transmitted by anti-neoplastic mechanism implanted in the cancer cells serve to obstruct the initial outgrowth of tumors. One such mechanism represents the action of the tumor suppressor protein PTEN, which negatively regulates Akt kinase activity. We provide the first evidence for significantly increased levels of PTEN in the tumors of simvastatin-administered mice. Importantly, simvastatin markedly prevented binding of NFkappaB to the two canonical recognition elements, NFRE-1 and NFRE-2 present in the PTEN promoter. Contrary to the transcriptional suppression of Bcl(XL), simvastatin significantly increased the transcription of PTEN. Furthermore, expression of NFkappaB p65 subunit inhibited transcription of PTEN, resulting in reduced protein expression, which leads to enhanced phosphorylation of Akt. Taken together, our data present a novel bifaceted mechanism where simvastatin acts on a nodal transcription factor NFkappaB, which attenuates the expression of anti-apoptotic Bcl(XL) and simultaneously derepresses the expression of anti-proliferative/proapoptotic tumor suppressor PTEN to prevent breast cancer cell growth.

journal_name

Cell Signal

journal_title

Cellular signalling

authors

Ghosh-Choudhury N,Mandal CC,Ghosh-Choudhury N,Ghosh Choudhury G

doi

10.1016/j.cellsig.2009.12.010

subject

Has Abstract

pub_date

2010-05-01 00:00:00

pages

749-58

issue

eissn

0898-6568

issn

1873-3913

pii

S0898-6568(10)00005-7

journal_volume

pub_type

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Simvastatin induces derepression of PTEN expression via NFkappaB to inhibit breast cancer cell growth.