[HTML][HTML] GGTase-I deficiency reduces tumor formation and improves survival in mice with K-RAS–induced lung cancer

AKM Sjogren, KME Andersson, M Liu… - The Journal of …, 2007 - Am Soc Clin Investig
AKM Sjogren, KME Andersson, M Liu, BA Cutts, C Karlsson, AM Wahlstrom, M Dalin…
The Journal of clinical investigation, 2007Am Soc Clin Investig
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 …
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 β 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.
The Journal of Clinical Investigation