Targeting Prenylated RAS Modifying Enzymes in Cancer Cells

Author(s): Yulong L. Chen.

Journal Name: Current Signal Transduction Therapy

Volume 1 , Issue 3 , 2006

Abstract:

RAS oncogenes have been identified in about 30% of all human cancers, particularly in 90% of human pancreatic cancers, 50% of colorectal tumors, and 30% of lung cancers. RAS is a central switch for many signal transduction pathways. The RAS proteins undergo three major posttranslational modification steps to become fully functional: prenylation (farnesylation or geranylgeranylation) of the cysteine residue of the CAAX of the RAS C-terminus (C, cysteine, A, aliphatic amino acid; X, Ser, Met, Glu, and Leu), endoproteolysis to remove the AAX amino acid sequence, and methylation of the newly formed prenylated cysteine C-terminus. It is hypothesized that any of these three steps could be an interference point for targeting RAS signaling to block the growth of the mutant RAS-dominant cancer cells. In the last decade, intensive efforts have been directed to target the prenylation of RAS, resulting in many RAS farnesylation inhibitors, which are in the clinical trials with mixed results. On the other hand, both recent chemical genetic and traditional genetic studies demonstrate that targeting two prenylation-dependent modification enzymes, RAS endoprotease and methyltransferase, might be two additional targets in killing mutant RAS-dependent cancer cells. This mini-review discusses the implications of both RAS endoprotease and methyltransferase as anticancer targets and their respective inhibitors as anticancer agents in cancer therapy.

Keywords: RAS, endoprotease, farnesyltransferase, methyltransferase, anticancer target, inhibitor

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Article Details

VOLUME: 1
ISSUE: 3
Year: 2006
Page: [285 - 293]
Pages: 9
DOI: 10.2174/157436206778226897
Price: $58

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