GGTase-I deficiency reduces tumor formation and improves survival in mice with K-RAS-induced lung cancer.
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.
Sjogren
Anna-Karin M
AK
Wallenberg Laboratory, Institute of Medicine, Sahlgrenska University Hospital, S-413 45 Göteborg, Sweden.
Andersson
Karin M E
KM
Liu
Meng
M
Cutts
Briony A
BA
Karlsson
Christin
C
Wahlstrom
Annika M
AM
Dalin
Martin
M
Weinbaum
Carolyn
C
Casey
Patrick J
PJ
Tarkowski
Andrej
A
Swolin
Birgitta
B
Young
Stephen G
SG
Bergo
Martin O
MO
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*
D019883:Alkyl and Aryl Transferases; C083291:geranylgeranyltransferase type-I; D018631:ras Proteins