Rho GTPase effectors and NAD metabolism in cancer immune suppression

Mahmoud Chaker, Audrey Minden, Suzie Chen, Robert H Weiss, Eduardo N. Chini, Amit Mahipal, Asfar S. Azmi

Research output: Contribution to journalReview article

6 Scopus citations

Abstract

Introduction: Sustained proliferative signaling and de-regulated cellular bioenergetics are two of the chief hallmarks of cancer. Alterations in the Ras pathway and its downstream effectors are among the major drivers for uncontrolled cell growth in many cancers. The GTPases are one of the signaling molecules that activate crucial signal transducing pathways downstream of Ras through several effector proteins. The GTPases (GTP bound) interact with several effectors and modulate a number of different biological pathways including those that regulate cytoskeleton, cellular motility, cytokinesis, proliferation, apoptosis, transcription and nuclear signaling. Similarly, the altered glycolytic pathway, the so-called ‘Warburg effect’, rewires tumor cell metabolism to support the biosynthetic requirements of uncontrolled proliferation. There exists strong evidence for the critical role of the glycolytic pathway’s rate limiting enzymes in promoting immunosuppression. Areas covered: We review the emerging roles of GTPase effector proteins particularly the p21 activated kinase 4 (PAK4) and nicotinamide biosynthetic pathway enzyme nicotinamide phosphoribosyltransferase (NAMPT) as signaling molecules in immune surveillance and the immune response. Expert opinion: In this expert opinion article we highlight the recent information on the role of GTPases and the metabolic enzymes on the immune microenvironment and propose some unique immune therapeutic opportunities.

Original languageEnglish (US)
Pages (from-to)9-17
Number of pages9
JournalExpert Opinion on Therapeutic Targets
Volume22
Issue number1
DOIs
StatePublished - Jan 2 2018

Keywords

  • GTPase
  • immune checkpoint
  • NAD
  • NAMPT
  • NAMPT inhibitor
  • NAPRT
  • P21 activated kinases
  • PAK4
  • PAK4 inhibitor
  • PD-1
  • PD-L1
  • Ras

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry

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