Targeting the protein prenyltransferases efficiently reduces tumor development in mice with K-RAS-induced lung cancer

Liu, Meng,1976Gothenburg University,Göteborgs universitet,Wallenberglaboratoriet,Wallenberg Laboratory (författare)

RAS and RHO proteins, which contribute to tumorigenesis and metastasis, undergo posttranslational modification with an isoprenyl lipid by protein farnesyltransferase (FTase) or protein geranylgeranyltransferase-I (GGTase-I). Inhibitors of FTase and GGTase-I were developed to block RAS-induced malignancies, but their utility has been difficult to evaluate because of off-target effects, drug resistance, and toxicity. Moreover, the impact of FTase deficiency and combined FTase/GGTase-I deficiency has not been evaluated with genetic approaches. We found that inactivation of FTase eliminated farnesylation of HDJ2 and H-RAS, prevented H-RAS targeting to the plasma membrane, and blocked proliferation of primary and K-RAS(G12D)-expressing fibroblasts. FTase inactivation in mice with K-RAS-induced lung cancer reduced tumor growth and improved survival, similar to results obtained previously with inactivation of GGTase-I. Simultaneous inactivation of FTase and GGTase-I markedly reduced lung tumors and improved survival without apparent pulmonary toxicity. These data shed light on the biochemical and therapeutic importance of FTase and suggest that simultaneous inhibition of FTase and GGTase-I could be useful in cancer therapeutics.

MEDICIN OCH HÄLSOVETENSKAP Medicinska och farmaceutiska grundvetenskaper Cell- och molekylärbiologi hsv//swe
MEDICAL AND HEALTH SCIENCES Basic Medicine Cell and Molecular Biology hsv//eng
Alkyl and Aryl Transferases/genetics/metabolism
Alleles
Animals
Cell Proliferation
Cell Transformation
Neoplastic/genetics/*metabolism
Dimethylallyltranstransferase/deficiency/*metabolism
Disease Models
Animal
Gene Expression Regulation
Enzymologic
Gene Expression Regulation
Neoplastic
Lung Neoplasms/*enzymology/genetics/pathology/therapy
Mice
Mice
Knockout
Mutation
Proto-Oncogene Proteins p21(ras)/genetics/*metabolism

Sjögren, Anna-Karin,1980Gothenburg University,Göteborgs universitet,Wallenberglaboratoriet,Wallenberg Laboratory(Swepub:gu)xsannz (författare)
Karlsson, Christin,1956Gothenburg University,Göteborgs universitet,Wallenberglaboratoriet,Wallenberg Laboratory(Swepub:gu)xkarlc (författare)
Ibrahim, Mohamed XGothenburg University,Göteborgs universitet,Wallenberglaboratoriet,Wallenberg Laboratory (författare)
Andersson, Karin,1972Gothenburg University,Göteborgs universitet,Wallenberglaboratoriet,Wallenberg Laboratory(Swepub:gu)xankar (författare)
Olofsson, Frida J,1982Gothenburg University,Göteborgs universitet,Wallenberglaboratoriet,Wallenberg Laboratory(Swepub:gu)xoloff (författare)
Wahlström, Annika,1975Gothenburg University,Göteborgs universitet,Wallenberglaboratoriet,Wallenberg Laboratory(Swepub:gu)xsannj (författare)
Dalin, Martin,1982Gothenburg University,Göteborgs universitet,Wallenberglaboratoriet,Wallenberg Laboratory(Swepub:gu)xdalim (författare)
Yu, Huiming (författare)
Chen, ZhenggangGothenburg University,Göteborgs universitet,Wallenberglaboratoriet,Wallenberg Laboratory (författare)
Yang, Shao H. (författare)
Young, Stephen G. (författare)
Bergö, Martin,1970Gothenburg University,Göteborgs universitet,Wallenberglaboratoriet,Wallenberg Laboratory(Swepub:gu)xbmarl (författare)
Göteborgs universitetWallenberglaboratoriet (creator_code:org_t)

Ingår i:Proceedings of the National Academy of Sciences of the United States of America: Proceedings of the National Academy of Sciences107:14, s. 6471-64760027-8424
Ingår i:Proceedings of the National Academy of Sciences: Proceedings of the National Academy of Sciences107:14, s. 6471-64761091-6490

Av författaren/redakt...: Liu, Meng, 1976; Sjögren, Anna-Ka ...; Karlsson, Christ ...; Ibrahim, Mohamed ...; Andersson, Karin ...; Olofsson, Frida ...; visa fler...; Wahlström, Annik ...; Dalin, Martin, 1 ...; Yu, Huiming; Chen, Zhenggang; Yang, Shao H.; Young, Stephen G ...; Bergö, Martin, 1 ...; visa färre...

Om ämnet

MEDICIN OCH HÄLSOVETENSKAP: MEDICIN OCH HÄLS ...; och Medicinska och f ...; och Cell och molekyl ...

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