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: Anna-Karin M Sjogren, Karin M E Andersson, Meng Liu, Briony A Cutts, Christin Karlsson, Annika M Wahlstrom, Martin Dalin, Carolyn Weinbaum, Patrick J Casey, Andrej Tarkowski, Birgitta Swolin, Stephen G Young, Martin O Bergo
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 117 Issue 5 Pg. 1294-304 (May 2007) ISSN: 0021-9738 [Print] United States
• PMID: 17476360 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Validation Study)

Chemical References

• Alkyl and Aryl Transferases
• geranylgeranyltransferase type-I
• ras Proteins

Topics

• Alkyl and Aryl Transferases (antagonists & inhibitors, deficiency, genetics)
• Animals
• Gene Silencing
• Lung Neoplasms (enzymology, genetics, mortality, prevention & control)
• Mice
• Survival (physiology)
• ras Proteins (toxicity)