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  • br Statins are clinically approved agents that


    Statins are clinically-approved agents that DTT 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 [13]. This suggests that 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 ( 119
    Original Article
    25-HC 25-hydroxycholesterol
    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
    MVA mevalonate
    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 [14] (Figure 1A). The en-zymes of the MVA pathway are transcriptionally regulated DTT by sterol regulatory element-binding protein 2 (SREBP2), which is activated in 
    response to intracellular sterol depletion. Aberrant SREBP2 expression and activity has been associated with PCa progression [15e17], suggesting that prostate tumors may be particularly dependent on cholesterol and other isoprenoid metabolites, and therefore vulnerable to HMGCR inhibition by statins. Statins have been shown to induce cancer cell-specific apoptosis in a number of different cancer cell types via the direct inhibition of HMGCR [5]; however, heterogeneous responses to statin exposure have been reported [18e21]. A number of mechanisms have been proposed to explain why some cancer cells are more sensitive to statins than others. For example, in breast cancer, high basal expression of sterol biosynthesis genes has been associated with resistance to atorvastatin [22]. Moreover, we previously demonstrated in multiple myeloma that lovastatin sensitivity was inversely associated with the ability of cells to induce the expression of MVA metabolism genes in response to statin exposure [23]. In PCa, however, the determinants of statin sensitivity remain to be defined.