Genome-wide RNAi analysis reveals that simultaneous inhibition of specific mevalonate pathway genes potentiates tumor cell death
Bibliographic record
Abstract
// Aleksandra A. Pandyra 1, 2, 4 , Peter J. Mullen 1 , Carolyn A. Goard 1, 2 , Elke Ericson 3, 5 , Piyush Sharma 4 , Manpreet Kalkat 1, 2 , Rosemary Yu 1, 2 , Janice T. Pong 1, 2 , Kevin R. Brown 3 , Traver Hart 3 , Marinella Gebbia 3 , Karl S. Lang 4 , Guri Giaever 3, 6 , Corey Nislow 3, 6 , Jason Moffat 3 , Linda Z. Penn 1, 2 1 Princess Margaret Cancer Centre, Toronto, ON, Canada 2 Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada 3 Donnelly Centre and Banting & Best Department of Medical Research, University of Toronto, Toronto, Canada 4 Institute of Immunology, Medical Faculty, University of Duisburg-Essen, Essen, Germany 5 Now located at AstraZeneca R&D, Mölndal Sweden 6 Now located at Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada Correspondence to: Linda Z. Penn, e-mail: lpenn@uhnres.utoronto.ca Keywords: SREBP2, statins, mevalonate pathway, feedback inhibition, tumor metabolism Received: June 17, 2015 Accepted: August 12, 2015 Published: August 22, 2015 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.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".