title: GGTase-I deficiency reduces tumor formation and improves survival in mice with K-RAS-induced lung cancer.
abstract: Protein geranylgeranyltransferase type I (GGTase-I) is responsible for the posttranslational lipidation of CAAX proteins such as RHOA, RAC1, and cell division cycle 42 (CDC42). Inhibition of GGTase-I has been suggested as a strategy to treat cancer and a host of other diseases. Although several GGTase-I inhibitors (GGTIs) have been synthesized, they have very different properties, and the effects of GGTIs and GGTase-I deficiency are unclear. One concern is that inhibiting GGTase-I might lead to severe toxicity. In this study, we determined the effects of GGTase-I deficiency on cell viability and K-RAS-induced cancer development in mice. Inactivating the gene for the critical beta subunit of GGTase-I eliminated GGTase-I activity, disrupted the actin cytoskeleton, reduced cell migration, and blocked the proliferation of fibroblasts expressing oncogenic K-RAS. Moreover, the absence of GGTase-I activity reduced lung tumor formation, eliminated myeloproliferative phenotypes, and increased survival of mice in which expression of oncogenic K-RAS was switched on in lung cells and myeloid cells. Interestingly, several cell types remained viable in the absence of GGTase-I, and myelopoiesis appeared to function normally. These findings suggest that inhibiting GGTase-I may be a useful strategy to treat K-RAS-induced malignancies.
authors.affiliation: Wallenberg Laboratory, Institute of Medicine, Sahlgrenska University Hospital, S-413 45 Göteborg, Sweden.
authors.forename: Anna-Karin M
authors.initials: AK
authors.lastname: Sjogren
authors.forename: Karin M E
authors.initials: KM
authors.lastname: Andersson
authors.forename: Meng
authors.initials: M
authors.lastname: Liu
authors.forename: Briony A
authors.initials: BA
authors.lastname: Cutts
authors.forename: Christin
authors.initials: C
authors.lastname: Karlsson
authors.forename: Annika M
authors.initials: AM
authors.lastname: Wahlstrom
authors.forename: Martin
authors.initials: M
authors.lastname: Dalin
authors.forename: Carolyn
authors.initials: C
authors.lastname: Weinbaum
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Casey
authors.forename: Andrej
authors.initials: A
authors.lastname: Tarkowski
authors.forename: Birgitta
authors.initials: B
authors.lastname: Swolin
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Young
authors.forename: Martin O
authors.initials: MO
authors.lastname: Bergo
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors / Q000172:deficiency* / Q000235:genetics*; D000818:Animals; D020868:Gene Silencing; D008175:Lung Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000401:mortality / Q000517:prevention & control*; D051379:Mice; D013534:Survival / Q000502:physiology*; D018631:ras Proteins / Q000633:toxicity*
chemical_list: D019883:Alkyl and Aryl Transferases; C083291:geranylgeranyltransferase type-I; D018631:ras Proteins