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

Nayana Ghosh-Choudhury, Chandi Charan Mandal, Nandini Ghosh-Choudhury, Goutam Ghosh Choudhury

Research output: Contribution to journalArticlepeer-review

147 Scopus citations


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 NFκB. Simvastatin inhibited the DNA binding and transcriptional activities of NFκB 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 NFκB 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 NFκB 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 NFκB, 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.

Original languageEnglish (US)
Pages (from-to)749-758
Number of pages10
JournalCellular Signalling
Issue number5
StatePublished - May 2010


  • Akt kinase
  • Bcl
  • Breast tumor
  • Statin

ASJC Scopus subject areas

  • Cell Biology


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