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A screen for inducers of bHLH activity identifies pitavastatin as a regulator of p21, Rb phosphorylation and E2F target gene expression in pancreatic cancer

Authors
 Nicholas Villarino  ;  Lia Signaevskaia  ;  Jaco van Niekerk  ;  Rachel Medal  ;  Heejung Kim  ;  Reyhaneh Lahmy  ;  Kathleen Scully  ;  Anthony Pinkerton  ;  Sangwun Kim  ;  Andrew Lowy  ;  Pamela Itkin-Ansari 
Citation
 ONCOTARGET, Vol.8(32) : 53154-53167, 2017-06 
Journal Title
ONCOTARGET
Issue Date
2017-06
Keywords
bHLH proteins ; drug discovery ; high throughput screening ; pancreatic cancer ; statins
Abstract
The average survival for patients with Pancreatic Ductal Adenocarcinoma (PDA) is merely 6 months, underscoring the need for new therapeutic approaches. During PDA progression, pancreatic acinar cells lose activity of the ClassI/II bHLH factors that regulate quiescence. We previously found that promoting transcriptional activity of the Class I bHLH factor E47 in highly aggressive PDA cells induced stable growth arrest in vitro and in vivo. To translate these findings for clinical utility, we developed a high throughput screening platform to identify small molecule inducers of Class I/II bHLH activity. A screen of 4,375 known drugs identified 70 bHLH activators. Prominent among the hits were members of the statin class of HMG-CoA reductase inhibitors, cholesterol lowering drugs that are also being evaluated in cancer. Studies with pitavastatin in primary patient derived tumor cells and established PDA lines, revealed dose dependent growth inhibition. At the molecular level, pitavastatin induced expression of the cyclin dependent kinase (CDK) inhibitor p21 in a cholesterol independent manner, blocked repressive phosphorylation of the Retinoblastoma tumor suppressor protein at CDK targeted sites, and reduced expression of E2F target genes required for progression through the G1/S boundary. Together, the data provide new insight into mechanisms by which statins constrain proliferation in cancer and establish the effectiveness of a novel screening platform to identify small molecules of clinical relevance in pancreatic cancer.
Files in This Item:
T992017177.pdf Download
DOI
10.18632/oncotarget.18587
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Obstetrics and Gynecology (산부인과학교실) > 1. Journal Papers
Yonsei Authors
Kim, Sang Wun(김상운) ORCID logo https://orcid.org/0000-0002-8342-8701
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/195853
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