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- Title
GGTase-I deficiency reduces tumor formation and improves survival in mice with K-RAS-induced lung cancer.
- Authors
Sjogren, Anna-Karin M.; Andersson, Karin M. E.; Meng Liu; Cutts, Briony A.; Karlsson, Christin; Wahlstrom, Annika M.; Dalin, Martin; Weinbaum, Carolyn; Casey, Patrick J.; Tarkowski, Andrej; Swolin, Birgitta; Young, Stephen G.; Bergo, Martin O.; Liu, Meng
- 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.
- Subjects
CANCER treatment; LUNG cancer; CYTOSKELETON formation; CELL growth; CELL migration; ANIMAL experimentation; COMPARATIVE studies; GENES; LUNG tumors; RESEARCH methodology; MEDICAL cooperation; MICE; PROTEINS; RESEARCH; RESEARCH funding; SURVIVAL; TRANSFERASES; EVALUATION research; PREVENTION
- Publication
Journal of Clinical Investigation, 2007, Vol 117, Issue 5, p1294
- ISSN
0021-9738
- Publication type
journal article
- DOI
10.1172/JCI30868