Lovastatin inhibits pancreatic cancer growth regardless of RAS mutation.
Lovastatin, an inhibitor of the rate-limiting enzyme of cholesterol synthesis, inhibits growth of pancreatic cancer cells. A possible mechanism of this inhibition is that lovastatin inhibits the activity of RAS protein by depleting farnesyl (an intermediate of cholesterol synthesis). The K-ras gene is frequently mutated in pancreatic cancers and RAS protein requires farnesyl to be bound to the cell membrane and thereby activated. To investigate whether lovastatin inhibition of cell growth depends upon the presence of ras mutation, codons 12/13 and 61 of ras genes were examined by the dideoxynucleotide chain-terminating method in five pancreatic cell lines (human CAPAN2, CAV, MIA Paca2, PANCi, and hamster H2T) on which lovastatin exerted a growth-inhibitory effect. These codons play a major role in tumorigenic mutation of ras genes. Lovastatin inhibited cell growth by 99% (MIA), 97% (H2T), 78% (CAV), 41% (CAPAN2), and 23% (PANC1), respectively, when cells were treated with 2.5 micrograms/ml lovastatin for 6 days. Activating point mutations were found in codon 12 of the K-ras gene (wild type:GGT) in MIA (GTT), H2T (GAT), CAPAN2 (TGT), and PANC1 (GAT) but not in CAV. In addition, the CAV cell line did not have a mutation in either H- or N-ras genes. Lovastatin inhibited the growth of CAV cells even though this cell line did not have ras mutation, suggesting that lovastatin inhibition of pancreatic cancer cell growth is not directly dependent on the presence of ras mutation.
Sumi
S
S
Department of Surgery, University of Texas Medical Branch, Galveston 77555-0533.
Beauchamp
R D
RD
Townsend
C M
CM
Pour
P M
PM
Ishizuka
J
J
Thompson
J C
JC
D000818:Animals; D001483:Base Sequence; D002455:Cell Division / Q000187:drug effects; D006224:Cricetinae; D011905:Genes, ras; D006801:Humans; D008148:Lovastatin / Q000494:pharmacology*; D008969:Molecular Sequence Data; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics; D017354:Point Mutation
D008148:Lovastatin