GGTase-I deficiency reduces tumor formation and improves survival in mice with K-RAS-induced lung cancer.

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Sjogren, A-KM; Andersson, KME; Liu, M; Cutts, BA; Karlsson, C; Wahlstrom, AM; Dalin, M; Weinbaum, C; Casey, PJ; Tarkowski, A; Swolin, B; Young, SG; Bergo, MO

Published Date

  • May 2007

Published In

Volume / Issue

  • 117 / 5

Start / End Page

  • 1294 - 1304

PubMed ID

  • 17476360

Pubmed Central ID

  • 17476360

International Standard Serial Number (ISSN)

  • 0021-9738

Digital Object Identifier (DOI)

  • 10.1172/JCI30868

Language

  • eng

Conference Location

  • United States