Targeting the Ras palmitoylation/depalmitoylation cycle in cancer

David Tse Shen Lin; Nicholas G Davis; Elizabeth Conibear

doi:10.1042/BST20160303

Targeting the Ras palmitoylation/depalmitoylation cycle in cancer

Biochem Soc Trans. 2017 Aug 15;45(4):913-921. doi: 10.1042/BST20160303. Epub 2017 Jun 19.

Authors

David Tse Shen Lin¹, Nicholas G Davis², Elizabeth Conibear³

Affiliations

¹ Centre for Molecular Medicine and Therapeutics, Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada V5Z 4H4.
² Department of Pharmacology, Wayne State University, Detroit, MI 48201, U.S.A.
³ Centre for Molecular Medicine and Therapeutics, Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada V5Z 4H4 conibear@cmmt.ubc.ca.

PMID: 28630138
DOI: 10.1042/BST20160303

Abstract

The Ras proteins are well-known drivers of many cancers and thus represent attractive targets for the development of anticancer therapeutics. Inhibitors that disrupt the association of the Ras proteins with membranes by blocking the addition of the farnesyl lipid moiety to the Ras C-terminus failed in clinical trials. Here, we explore the possibility of targeting a second lipid modification, S-acylation, commonly referred to as palmitoylation, as a strategy to disrupt the membrane interaction of specific Ras isoforms. We review the enzymes involved in adding and removing palmitate from Ras and discuss their potential roles in regulating Ras tumorigenesis. In addition, we examine other proteins that affect Ras protein localization and may serve as future drug targets.

Keywords: ABHD17A; ABHD17B; ABHD17C; APT1; palmostatin B; thioesterase.

Publication types

Review

MeSH terms

Acyltransferases / antagonists & inhibitors*
Acyltransferases / metabolism
Animals
Antineoplastic Agents / therapeutic use*
Carcinogenesis / drug effects
Carcinogenesis / metabolism
Cysteine / metabolism
Enzyme Activation / drug effects
Enzyme Inhibitors / therapeutic use
Humans
Hydrolysis / drug effects
Isoenzymes / antagonists & inhibitors
Isoenzymes / metabolism
Lipoylation / drug effects
Molecular Targeted Therapy* / trends
Mutation
Neoplasm Proteins / antagonists & inhibitors
Neoplasm Proteins / genetics
Neoplasm Proteins / metabolism
Neoplasms / drug therapy*
Neoplasms / genetics
Neoplasms / metabolism
Neoplasms / prevention & control
Protein Processing, Post-Translational / drug effects*
Protein Transport / drug effects
Thiolester Hydrolases / antagonists & inhibitors*
Thiolester Hydrolases / metabolism
ras Proteins / genetics
ras Proteins / metabolism*

Substances

Antineoplastic Agents
Enzyme Inhibitors
Isoenzymes
Neoplasm Proteins
Acyltransferases
Thiolester Hydrolases
palmitoyl-protein thioesterase
ras Proteins
Cysteine