Research Papers:

Genome-wide RNAi analysis reveals that simultaneous inhibition of specific mevalonate pathway genes potentiates tumor cell death

Aleksandra A. Pandyra, Peter J. Mullen, Carolyn A. Goard, Elke Ericson, Piyush Sharma, Manpreet Kalkat, Rosemary Yu, Janice T. Pong, Kevin R. Brown, Traver Hart, Marinella Gebbia, Karl S. Lang, Guri Giaever, Corey Nislow, Jason Moffat and Linda Z. Penn _

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Oncotarget. 2015; 6:26909-26921. https://doi.org/10.18632/oncotarget.4817

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Aleksandra A. Pandyra1,2,4, Peter J. Mullen1, Carolyn A. Goard1,2, Elke Ericson3,5, Piyush Sharma4, Manpreet Kalkat1,2, Rosemary Yu1,2, Janice T. Pong1,2, Kevin R. Brown3, Traver Hart3, Marinella Gebbia3, Karl S. Lang4, Guri Giaever3,6, Corey Nislow3,6, Jason Moffat3, Linda Z. Penn1,2

1Princess Margaret Cancer Centre, Toronto, ON, Canada

2Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada

3Donnelly Centre and Banting & Best Department of Medical Research, University of Toronto, Toronto, Canada

4Institute of Immunology, Medical Faculty, University of Duisburg-Essen, Essen, Germany

5Now located at AstraZeneca R&D, Mölndal Sweden

6Now located at Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada

Correspondence to:

Linda Z. Penn, e-mail: [email protected]

Keywords: SREBP2, statins, mevalonate pathway, feedback inhibition, tumor metabolism

Received: June 17, 2015     Accepted: August 12, 2015     Published: August 22, 2015


The mevalonate (MVA) pathway is often dysregulated or overexpressed in many cancers suggesting tumor dependency on this classic metabolic pathway. Statins, which target the rate-limiting enzyme of this pathway, 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), are promising agents currently being evaluated in clinical trials for anti-cancer efficacy. To uncover novel targets that potentiate statin-induced apoptosis when knocked down, we carried out a pooled genome-wide short hairpin RNA (shRNA) screen. Genes of the MVA pathway were amongst the top-scoring targets, including sterol regulatory element binding transcription factor 2 (SREBP2), 3-hydroxy-3-methylglutaryl-coenzyme A synthase 1 (HMGCS1) and geranylgeranyl diphosphate synthase 1 (GGPS1). Each gene was independently validated and shown to significantly sensitize A549 cells to statin-induced apoptosis when knocked down. SREBP2 knockdown in lung and breast cancer cells completely abrogated the fluvastatin-induced upregulation of sterol-responsive genes HMGCR and HMGCS1. Knockdown of SREBP2 alone did not affect three-dimensional growth of lung and breast cancer cells, yet in combination with fluvastatin cell growth was disrupted. Taken together, these results show that directly targeting multiple levels of the MVA pathway, including blocking the sterol-feedback loop initiated by statin treatment, is an effective and targetable anti-tumor strategy.

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