br Results High HMGCR expression
Results: High HMGCR Ferrostatin-1 in PCa was associated with poor prognosis; however, not all PCa cell lines underwent apoptosis in response to treatment with physiologically-achievable concentrations of fluvastatin. Rather, most cell lines initiated a feedback response mediated by sterol regulatory element-binding protein 2 (SREBP2), which led to the further upregulation of HMGCR and other lipid metabolism genes. Overcoming this feedback mechanism by knocking down or inhibiting SREBP2 potentiated fluvastatin-induced PCa cell death. Notably, we demonstrated that this feedback loop is pharmacologically-actionable, as the drug dipyridamole can be used to block fluvastatin-induced SREBP activation and augment apoptosis in statin-insensitive PCa cells.
Conclusion: Our study implicates statin-induced SREBP2 activation as a PCa vulnerability that can be exploited for therapeutic purposes using clinically-approved agents.
2019 University Health Network. Published by Elsevier GmbH. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Keywords Statins; Dipyridamole; Prostate cancer; Mevalonate pathway; Tumor metabolism; Drug repurposing
Prostate cancer (PCa) is the most commonly diagnosed malignancy in men and the third-leading cause of cancer-related male mortality in developed countries . Given the long natural history of PCa, many patients suffer from disease-related morbidity and compromised quality of life, due in part to side-effects of radical therapies such as androgen deprivation . An estimated 20e50% of PCa patients relapse after frontline treatment and inevitably progress to more advanced, lethal forms of the disease . Hence, there is an unmet need for safe and effective therapies to treat PCa and delay disease progression.
Statins are clinically-approved agents that are commonly prescribed for the management of high cholesterol, but more recently have been
shown to possess anti-cancer properties [4,5]. A number of retro-spective studies have reported an association between statin medi-cation use and reduced PCa risk, particularly more advanced and lethal forms of the disease [6e9]. In addition to chemoprevention, statin use has been associated with improved patient outcome following radical therapy [10e12]; however, studies are conflicting as to the extent to which statin use at the time of frontline therapy improves patient outcome . This suggests periosteum a subset of PCa patients may benefit from the addition of statins to their treatment regimen, and, in other patients, additional targeted agents may be required to improve patient responses to statin therapy.
Statins are specific inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (HMGCR), the rate-limiting enzyme of the mevalonate (MVA) pathway. The MVA pathway is an integral metabolic
1Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, M5G 1L7, Canada 2Department of Medical Biophysics, University of Toronto, Toronto, Ontario, M5G 1L7, Canada 3Department of Pathology, Laboratory Medicine Program, University Health Network, Toronto, Ontario, M5G 2C4, Canada 4Division of Urology, Department of Surgical Oncology, University Health Network & University of Toronto, Toronto, Ontario, M5G 2M9, Canada 5Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, V6H 3Z6, Canada 6Department of Experimental Therapeutics, BC Cancer Research Centre, Vancouver, British Columbia, V5Z 1L3, Canada
*Corresponding author. Princess Margaret Cancer Research Tower, 101 College Street, 13-706, Toronto, Ontario, M5G 1L7, Canada. E-mail: [email protected] (L.Z. Penn).
MOLECULAR METABOLISM 25 (2019) 119e1302019 University Health Network. Published by Elsevier GmbH. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). 119 www.molecularmetabolism.com
BCR biochemical relapse
FPP farnesyl pyrophosphate
GGPP geranylgeranyl pyrophosphate
HMG-CoA 3-hydroxy-3-methylglutaryl coenzyme A HMGCR HMG-CoA reductase HMGCS1 HMG-CoA synthase 1 IC50 half-maximal inhibitory concentration
INSIG1 insulin-induced gene 1
PCa prostate cancer
PDX patient-derived xenograft
PSA prostate-specific antigen
RP radical prostatectomy
SCD stearoyl-CoA desaturase
SREBP sterol regulatory element-binding protein
TMA tissue microarray
pathway that converts acetyl-CoA to sterols and other isoprenoids that are important for cell growth and survival  (Figure 1A). The en-zymes of the MVA pathway are transcriptionally regulated by sterol regulatory element-binding protein 2 (SREBP2), which is activated in