title: Driven to death: Inhibition of farnesylation increases Ras activity and promotes growth arrest and cell death [corrected].
abstract: To improve cancer outcomes, investigators are turning increasingly to small molecule medicines that disrupt vital signaling cascades, inhibit malignant growth, or induce apoptosis. One vital signaling molecule is Ras, and a key step in Ras activation is membrane anchoring of Ras through prenylation, the C-terminal addition of a lipid anchor. Small molecule inhibitors of farnesyltransferase (FTI), the enzyme most often responsible for prenylating Ras, showed clinical promise, but development of FTIs such as tipifarnib has been stalled by uncertainty about their mechanism of action, because Ras seemed unimpeded in tipifarnib-treated samples. Interpretation was further complicated by the numerous proteins that may be farnesylated, as well as availability of an alternate prenylation pathway, geranylgeranylation. Our initial observations of varied response by cancer cell lines to tipifarnib led us to evaluate the role of FTI in Ras signal alteration using various tumor models. We describe our novel counterintuitive finding that endogenous Ras activity increases in cancer cell lines with low endogenous Ras activity when farnesyltransferase is inhibited by either tipifarnib or short hairpin RNA. In response to tipifarnib, variable growth arrest and/or cell death correlated with levels of activated extracellular signal–regulated kinase (ERK) and p38 mitogenactivated protein kinase (MAPK). Sensitivity to tipifarnib treatment was shown by growth inhibition and by an increase in subdiploid cell numbers; cells with such sensitivity had increased activation of ERK and p38 MAPK. Because Ras must be prenylated to be active, our findings suggest that geranylgeranylated N-Ras or K-Ras B interacts differently with downstream effector proteins in sensitive cancer cells responding to tipifarnib, switching the balance from cell proliferation to growth inhibition [corrected].
authors.affiliation: Department of Pediatrics Research, Children's Cancer Hospital, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Mandy
authors.initials: M
authors.lastname: Geryk-Hall
authors.forename: Yanwen
authors.initials: Y
authors.lastname: Yang
authors.forename: Dennis P M
authors.initials: DP
authors.lastname: Hughes
mesh_terms: D000293:Adolescent; D000970:Antineoplastic Agents / Q000494:pharmacology; D001859:Bone Neoplasms / Q000378:metabolism / Q000473:pathology*; D002453:Cell Cycle / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008297:Male; D012516:Osteosarcoma / Q000378:metabolism / Q000473:pathology*; D015363:Quinolones / Q000494:pharmacology*; D020298:U937 Cells; D015854:Up-Regulation / Q000187:drug effects; D018631:ras Proteins / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D015363:Quinolones; D051231:Farnesyltranstransferase; D018631:ras Proteins; C402769:tipifarnib
references.citation: J Cell Biochem. 2004 Jun 1;92(3):514-24
references.pmid: 15156563
references.citation: Cancer Res. 2004 Apr 15;64(8):2759-65
references.pmid: 15087391
references.citation: J Cell Sci. 2002 Mar 15;115(Pt 6):1189-202
references.pmid: 11884518
references.citation: J Lipid Res. 1992 Dec;33(12):1731-40
references.pmid: 1479283
references.citation: Clin Cancer Res. 2008 Oct 15;14(20):6396-404
references.pmid: 18927278
references.citation: Cancer Res. 2005 Oct 15;65(20):9109-12
references.pmid: 16230362
references.citation: J Biol Chem. 1994 Jan 14;269(2):1276-83
references.pmid: 8288590
references.citation: Cancer Genet Cytogenet. 1995 Jan;79(1):49-53
references.pmid: 7850751
references.citation: J Biol Chem. 1997 May 30;272(22):14459-64
references.pmid: 9162087
references.citation: J Biol Chem. 2000 Sep 29;275(39):30451-7
references.pmid: 10852915
references.citation: Mol Cancer Ther. 2006 Oct;5(10):2512-21
references.pmid: 17041095
references.citation: J Biol Chem. 2003 Jul 25;278(30):28045-51
references.pmid: 12732644
references.citation: Sci STKE. 2002 Oct 01;2002(152):pe41
references.pmid: 12359913
references.citation: J Cell Biochem. 2006 Feb 1;97(2):412-22
references.pmid: 16187291
references.citation: Int J Biochem Cell Biol. 1998 Nov;30(11):1203-21
references.pmid: 9839446
references.citation: Clin Cancer Res. 2008 May 15;14(10):2962-9
references.pmid: 18483362
references.citation: Cell. 1997 Mar 7;88(5):593-602
references.pmid: 9054499
references.citation: Traffic. 2006 Sep;7(9):119-26
references.pmid: 16824054
references.citation: FASEB J. 2008 Apr;22(4):954-65
references.pmid: 18039929
references.citation: Arch Dis Child. 2005 May;90(5):494-9
references.pmid: 15851432
references.citation: Blood. 2003 Dec 1;102(12):3880-9
references.pmid: 12920034
references.citation: Oncogene. 1998 Mar;16(11):1467-73
references.pmid: 9525745
references.citation: Exp Cell Res. 2002 Feb 15;273(2):138-46
references.pmid: 11822869
references.citation: Proc Natl Acad Sci U S A. 1996 Apr 16;93(8):3636-41
references.pmid: 8622988
references.citation: Cancer Res. 2003 Sep 15;63(18):5656-68
references.pmid: 14522880
references.citation: J Biol Inorg Chem. 2005 Jan;10(1):3-10
references.pmid: 15611883
references.citation: Pediatr Blood Cancer. 2006 May 1;46(5):614-23
references.pmid: 16007579
references.citation: Methods Enzymol. 2001;333:348-55
references.pmid: 11400351
references.citation: J Clin Oncol. 2000 Feb;18(4):927-41
references.pmid: 10673536
references.citation: J Biol Chem. 2000 Jul 28;275(30):22916-24
references.pmid: 10781597
references.citation: Biochemistry. 2004 Jun 8;43(22):6877-84
references.pmid: 15170324
references.citation: Mol Cell. 2006 Feb 17;21(4):481-93
references.pmid: 16483930
references.citation: Cancer Res. 2006 Jul 1;66(13):6756-62
references.pmid: 16818651
references.citation: Cancer Res. 2005 Apr 1;65(7):2861-71
references.pmid: 15805288
references.citation: Clin Cancer Res. 2006 Jan 15;12(2):591-9
references.pmid: 16428505
references.citation: Genome Biol. 2005;6(6):R55
references.pmid: 15960807
references.citation: Cancer Res. 2006 Jan 15;66(2):1040-51
references.pmid: 16424040
references.citation: BMC Cancer. 2004 Aug 25;4:56
references.pmid: 15329151
references.citation: J Lipid Res. 2006 Jan;47(1):15-31
references.pmid: 16278491
references.citation: Blood. 2008 Mar 1;111(5):2589-96
references.pmid: 18160667
references.citation: J Cell Physiol. 2007 May;211(2):533-43
references.pmid: 17192846
references.citation: Nat Rev Cancer. 2005 May;5(5):405-12
references.pmid: 15864282
references.citation: J Natl Cancer Inst. 2001 Jul 18;93(14):1062-74
references.pmid: 11459867
references.citation: Mol Cancer Res. 2005 Oct;3(10):563-74
references.pmid: 16254190
references.citation: Microbiol Mol Biol Rev. 2004 Jun;68(2):320-44
references.pmid: 15187187
references.citation: Clin Orthop Relat Res. 2008 Sep;466(9):2071-80
references.pmid: 18516656