Inhibition of HMGcoA reductase by atorvastatin prevents and reverses MYC-induced lymphomagenesis.
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. Thus, atorvastatin, by inhibiting HMGcoA reductase, induces changes in phosphoprotein signaling that in turn prevent MYC-induced lymphomagenesis.
Shachaf
Catherine M
CM
Division of Medical Oncology, Department of Medicine, Stanford University, Stanford, CA 94305-5151, USA.
Perez
Omar D
OD
Youssef
Sawsan
S
Fan
Alice C
AC
Elchuri
Sailaja
S
Goldstein
Matthew J
MJ
Shirer
Amy E
AE
Sharpe
Orr
O
Chen
Joy
J
Mitchell
Dennis J
DJ
Chang
Maria
M
Nolan
Garry P
GP
Steinman
Lawrence
L
Felsher
Dean W
DW
D000818:Animals; D000069059:Atorvastatin; D002470:Cell Survival; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002478:Cells, Cultured; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D005998:Glycine / Q000235:genetics / Q000378:metabolism; D006538:Heptanoic Acids / Q000494:pharmacology*; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008223:Lymphoma / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D016274:Oncogene Protein p55(v-myc) / Q000235:genetics / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D011230:Precancerous Conditions / Q000473:pathology; D011758:Pyrroles / Q000494:pharmacology*; D015398:Signal Transduction; D015996:Survival Rate; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D016274:Oncogene Protein p55(v-myc); D010750:Phosphoproteins; D011758:Pyrroles; D000069059:Atorvastatin; D006903:Hydroxymethylglutaryl CoA Reductases; D018631:ras Proteins; D005998:Glycine