Inhibition of HMGcoA reductase by atorvastatin prevents and reverses MYC-induced lymphomagenesis

Abstract

Statins are a class of drugs that inhibit 3-hydroxy-3-methylglutaryl-coenzyme A (HMGcoA) reductase, a critical enzyme in the mevalonate pathway. Several reports document that statins may prevent different human cancers. However, whether or not statins can prevent cancer is controversial due to discordant results. One possible explanation for these conflicting conclusions is that only some tumors or specific statins may be effective. Here, we demonstrate in an in vivo transgenic model in which atorvastatin reverses and prevents the onset of MYC-induced lymphomagenesis, but fails to reverse or prevent tumorigenesis in the presence of constitutively activated K-Ras (G12D). Using phosphoprotein fluorescence-activated cell sorter (FACS) analysis, atorvastatin treatment was found to result in the inactivation of the Ras and ERK1/2 signaling pathways associated with the dephosphorylation and inactivation of MYC. Correspondingly, tumors with a constitutively activated K-Ras (G12D) did not exhibit dephosphorylation of ERK1/2 and MYC. Atorvastatin's effects on MYC were specific to the inhibition of HMGcoA reductase, as treatment with mevalonate, the product of HMG-CoA reductase activity, abrogated these effects and inhibited the ability of atorvastatin to reverse or suppress tumorigenesis. Also, RNAi directed at HMGcoA reductase was sufficient to abrogate the neoplastic properties of MYC-induced tumors. IntroductionCancer is largely caused by genomic events which result in the activation of oncogenes or the loss of tumor-suppressor genes. 1 The targeted inactivation of oncogenes may be a specific and effective therapy for treating certain malignancies. 2,3 Experimental results in animal models validate the notion that the targeted inactivation of a single oncogene can be sufficient to reverse tumorigenesis. 4 Drugs that target specific proteins have been identified and shown to be effective in the treatment of certain cancers, [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21] which indicates that some neoplasms are susceptible to therapies that target their molecular causes. However, cancers can escape dependence upon oncogenes, as observed in animal models as well as in human patients. [21][22][23] Thus, the best targets may not be the suspected oncogenes but rather proteins essential to multiple signaling or metabolic pathways required for tumor maintenance.MYC is one of the oncogenes most commonly associated with human cancer. 24 Experimentally, the inactivation of MYC has been shown to induce sustained tumor regression in transgenic mouse models of many different tumors, suggesting that MYC may be a good target for cancer treatment. [25][26][27][28] However, MYC as a transcription factor is not easy to target directly with small molecules. Thus, rather than directly targeting MYC, it might be possible to inactivate MYC through the disruption of upstream regulatory signaling molecules such as those in pathways regulated by Ras and ERK1/2. 29,30 The enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (HMGcoA) r...

MYC Activation Is a Hallmark of Cancer Initiation and Maintenance

“…Nevertheless, several reports suggest that small interfering RNA, short hairpin RNA, and antisense oligonucleotides could be potential strategies to target MYC (Hermeking 2003;Pastorino et al 2004;Vita and Henriksson 2006). Therapies that briefly or even partially suppress MYC directly or indirectly may be highly effica- cious in the reversal of neoplasia, for example, as illustrated by inhibition via statins or BRD4 inhibition (Shachaf et al 2007;Cao et al 2011;Delmore et al 2011;McKeown and Bradner 2014). Alternatively, synthetic lethal screens may identify therapeutic strategies to target MYC-addicted tumors Kessler et al 2012;Toyoshima et al 2012;Cermelli et al 2014).…”

Long-term Use of Cholesterol-Lowering Drugs and Cancer Incidence in a Large United States Cohort

“…A causal association between use of cholesterol-lowering drugs and NHL is biologically plausible. Statins have been shown to inhibit lymphoma in mouse models (49)(50)(51). Statins also have antiinflammatory effects, demonstrated by substantial reductions in C-reactive protein (a marker of systemic inflammation) at clinically used doses (6)(7)(8), that could be relevant given the role of chronic inflammation in NHL etiology (52).…”

Noninvasive molecular imaging of c-Myc activation in living mice

“…7D). There are various conditional mutant Myc transgenic mice in which overexpression of WT or mutant Myc is reversible under control of the Tet system (13,(29)(30)(31)(32). Crossing the sensor transgenic mice to these conditional mutant Myc transgenic mice can allow the noninvasive study of the relationship between Myc gene deregulation and Myc protein activation in the induction and maintenance of tumorigenesis in different tumor models.…”

“…ERK kinase inhibitors PD98059 and U0126 decrease the c-Myc phosphorylation level in vitro (12), but there has been no study of their effect on tumor growth. Atorvastatin (AT), a member of the statin family, was unexpectedly found to reduce phosphorylation of c-Myc by inhibiting 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-coA) reductase and in turn preventing c-Myc-induced lymphomagenesis (13), although the exact molecular mechanism remains unclear. The unavailability of methods to noninvasively monitor c-Myc activity has hindered further understanding of Myc cancer biology and contributed to delays in c-Myc-targeted drug development (14).…”