Nanoscale Proteomic Analysis of Oncoproteins in Hematopoietic Cancers
نویسندگان
چکیده
MYC is a potential target for many cancers but is not amenable to existing pharmacologic approaches.Inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase) by statins has shownpotential efficacy against a number of cancers. Here, we show that inhibition of HMG-CoA reductase byatorvastatin (AT) blocks both MYC phosphorylation and activation, suppressing tumor initiation and growthin vivo in a transgenic model of MYC-induced hepatocellular carcinoma (HCC) as well as in human HCC-derivedcell lines. To confirm specificity, we show that the antitumor effects of AT are blocked by cotreatment with theHMG-CoA reductase product mevalonate. Moreover, by using a novel molecular imaging sensor, we confirmthat inhibition of HMG-CoA reductase blocks MYC phosphorylation in vivo. Importantly, the introduction ofphosphorylation mutants of MYC at Ser62 or Thr58 into tumors blocks their sensitivity to inhibition of HMG-CoA reductase. Finally, we show that inhibition of HMG-CoA reductase suppresses MYC phosphorylationthrough Rac GTPase. Therefore, HMG-CoA reductase is a critical regulator of MYC phosphorylation, activation,and tumorigenic properties. The inhibition of HMG-CoA reductase may be a useful target for the treatment ofMYC-associated HCC as well as other tumors. Cancer Res; 71(6); 2286–97. 2011 AACR.
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