Format

Send to

Choose Destination
Oncotarget. 2015 Sep 29;6(29):26909-21. doi: 10.18632/oncotarget.4817.

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

Author information

1
Princess Margaret Cancer Centre, Toronto, ON, Canada.
2
Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
3
Institute of Immunology, Medical Faculty, University of Duisburg-Essen, Essen, Germany.
4
Donnelly Centre and Banting & Best Department of Medical Research, University of Toronto, Toronto, ON, Canada.
5
Now located at AstraZeneca R&D, Mölndal, Sweden.
6
Now located at Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada.

Abstract

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.

KEYWORDS:

SREBP2; feedback inhibition; mevalonate pathway; statins; tumor metabolism

PMID:
26353928
PMCID:
PMC4694962
DOI:
10.18632/oncotarget.4817
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Impact Journals, LLC Icon for PubMed Central
Loading ...
Support Center