MYC phosphorylation, activation, and tumorigenic potential in hepatocellular carcinoma are regulated by HMG-CoA reductase.
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 shown potential efficacy against a number of cancers. Here, we show that inhibition of HMG-CoA reductase by atorvastatin (AT) blocks both MYC phosphorylation and activation, suppressing tumor initiation and growth in vivo in a transgenic model of MYC-induced hepatocellular carcinoma (HCC) as well as in human HCC-derived cell lines. To confirm specificity, we show that the antitumor effects of AT are blocked by cotreatment with the HMG-CoA reductase product mevalonate. Moreover, by using a novel molecular imaging sensor, we confirm that inhibition of HMG-CoA reductase blocks MYC phosphorylation in vivo. Importantly, the introduction of phosphorylation 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 phosphorylation through 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 of MYC-associated HCC as well as other tumors.
Division of Medical Oncology, Department of Medicine and Pathology, Molecular Imaging Program at Stanford, Stanford University, Stanford, California 94305, USA.
Zhongwei
Z
Cao
Hua
H
Fan-Minogue
David I
DI
Bellovin
Aleksey
A
Yevtodiyenko
Julia
J
Arzeno
Qiwei
Q
Yang
Sanjiv Sam
SS
Gambhir
Dean W
DW
Felsher
D000818:Animals; D000069059:Atorvastatin; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D056945:Hep G2 Cells; D006538:Heptanoic Acids / Q000494:pharmacology; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D015151:Immunoblotting; D053208:Kaplan-Meier Estimate; D008113:Liver Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D008822:Mice, Transgenic; D009154:Mutation; D010766:Phosphorylation / Q000187:drug effects; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D011758:Pyrroles / Q000494:pharmacology; D012694:Serine / Q000235:genetics / Q000378:metabolism; D013912:Threonine / Q000235:genetics / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D020744:rac GTP-Binding Proteins / Q000378:metabolism
D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D011758:Pyrroles; D013912:Threonine; D012694:Serine; D000069059:Atorvastatin; D006903:Hydroxymethylglutaryl CoA Reductases; D020744:rac GTP-Binding Proteins
Drug Metab Dispos. 1998 Aug;26(8):755-63
9698289
Cancer Res. 1958 Aug;18(7):853-6
13573353
Leukemia. 2002 Apr;16(4):508-19
11960327
Carcinogenesis. 2002 Mar;23(3):521-8
11895868
Hepatogastroenterology. 2004 Jul-Aug;51(58):1099-103
15239254
Menopause. 2003 Jul-Aug;10(4):332-6
12851516
Cell Signal. 2003 Mar;15(3):327-38
12531431
Circulation. 2002 Feb 12;105(6):739-45
11839631
Anal Chem. 2003 Apr 1;75(7):1584-9
12705589
Br J Cancer. 2001 Apr 6;84(7):886-91
11286466
Nat Genet. 2004 Dec;36(12):1306-11
15565109
J Exp Med. 2008 Jan 21;205(1):91-103
18158318
Carcinogenesis. 2001 Aug;22(8):1139-48
11470741
Blood. 2007 Oct 1;110(7):2674-84
17622571
Curr Mol Med. 2003 Sep;3(6):573-88
14527088
Nat Med. 2000 Sep;6(9):1004-10
10973320
Jpn J Cancer Res. 1996 Aug;87(8):798-804
8797885
Nat Rev Cancer. 2006 Sep;6(9):674-87
16929323
Nat Rev Cancer. 2005 Dec;5(12):930-42
16341084
Toxicol Lett. 2000 Mar 15;112-113:553-5
10720779
Carcinogenesis. 2004 Oct;25(10):1887-98
15180944
Nat Genet. 1993 Sep;5(1):56-61
8220424
J Nutr. 1997 May;127(5):668-74
9164984
Biochem Biophys Res Commun. 2004 Jul 16;320(1):165-9
15207716
Cancer Res. 2009 Apr 1;69(7):2775-82
19276364
Oncogene. 1993 Dec;8(12):3199-209
8247524
Mol Cell Biol. 1994 Aug;14(8):5510-22
8035827
Hepatology. 2006 Feb;43(2 Suppl 1):S45-53
16447274
EMBO J. 2007 Jan 24;26(2):336-45
17245428
Cancer Prev Res (Phila). 2009 Feb;2(2):161-7
19196723
J Clin Invest. 2001 Oct;108(7):981-90
11581299
Gastroenterology. 1999 Oct;117(4):838-47
10500066
Gene Ther. 1999 Jul;6(7):1258-66
10455434
J Biol Chem. 1996 Mar 8;271(10):5513-8
8621409
FASEB J. 2008 Mar;22(3):659-61
17942826
FASEB J. 2005 Sep;19(11):1513-5
15990392
Nat Cell Biol. 2004 Apr;6(4):308-18
15048125
Nature. 2004 Oct 28;431(7012):1112-7
15475948
Nat Rev Mol Cell Biol. 2005 Aug;6(8):635-45
16064138
Subcell Biochem. 1997;28:1-21
9090289
J Clin Oncol. 2009 Mar 20;27(9):1485-91
19224838
Clin Cancer Res. 2003 Jan;9(1):10-9
12538446
Proc Natl Acad Sci U S A. 2010 Sep 7;107(36):15892-7
20713710
Nature. 1990 Feb 1;343(6257):425-30
1967820
J Biol Chem. 2003 Dec 19;278(51):51606-12
14563837
Genes Dev. 2000 Oct 1;14(19):2501-14
11018017
Digestion. 2008;78(1):34-8
18797167
Clin Cancer Res. 2000 May;6(5):2044-52
10815931
Proc Natl Acad Sci U S A. 1991 May 1;88(9):3628-32
1673788
EMBO J. 1999 Feb 1;18(3):717-26
9927431
Nat Cell Biol. 2001 Jun;3(6):580-6
11389443
Oncologist. 2006 Mar;11(3):306-15
16549815