A screen for inducers of bHLH activity identifies pitavastatin as a regulator of p21, Rb phosphorylation and E2F target gene expression in pancreatic cancer
Metrics: PDF 1451 views | HTML 3497 views | ?
Nicholas Villarino1, Lia Signaevskaia1, Jaco van Niekerk1, Rachel Medal1, Heejung Kim1, Reyhaneh Lahmy1, Kathleen Scully1, Anthony Pinkerton2, Sangwun Kim3, Andrew Lowy4 and Pamela Itkin-Ansari1,5
1Development, Aging and Regeneration Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA
2Conrad Prebys Center for Chemical Genomics, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA
3Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Institute of Women's Life Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea
4Departments of Pathology and Surgery, Division of Surgical Oncology, Moores UCSD Cancer Center, University of California San Diego, La Jolla, CA, USA
5Department of Pediatrics, University of California San Diego, La Jolla, CA, USA
Pamela Itkin-Ansari, email: email@example.com
Keywords: bHLH proteins, pancreatic cancer, high throughput screening, drug discovery, statins
Received: March 15, 2017 Accepted: May 23, 2017 Published: June 21, 2017
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.
All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.