Linking stress-signaling, glutathione metabolism, signaling pathways and xenobiotic transporters

Cancer Metastasis Rev. 2007 Mar;26(1):59-69. doi: 10.1007/s10555-007-9043-5.

Abstract

Multi-specific drug-transport mechanisms are intricately involved in mediating a pleiotropic drug-resistance in cancer cells by mediating drug-accumulation defects in cells in which they are over-expressed. The existence and over-expression in drug-resistant neoplasms of transporter proteins belonging to ATP-binding cassette (ABC) family indicate that these myriad transporters contribute to the multidrug-resistance phenomena by removing or sequestering of toxins and metabolites. Another prominent mechanism of multispecific drug-resistance involves glutathione and glutathione linked enzymes, particularly those of the mercapturic acid pathway, which are involved in metabolism and excretion of both endogenous and exogenous electrophilic toxins. A key step in the mercapturic acid pathway, efflux of the glutathione-electrophile conjugate has recently been shown to be catalyzed largely by the stress-responsive protein RLIP76, a splice variant peptide endowed by the human gene RALBP1. The known involvement of RLIP76 in membrane signaling pathways and endocytosis has resulted in a new paradigm for transport and metabolism related drug-resistance in which RLIP76 plays a central role. Our recent studies demonstrating a key anti-apoptotic and stress-responsive role of RLIP76, and the demonstration of dramatic response in malignancies to RLIP76 depletion indicate that targeting this mercapturic acid pathway transporter may be a highly effective and multifaceted antineoplastic strategy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • ATP-Binding Cassette Transporters / antagonists & inhibitors
  • ATP-Binding Cassette Transporters / genetics
  • ATP-Binding Cassette Transporters / metabolism*
  • Acetylcysteine / metabolism*
  • Drug Resistance, Neoplasm* / genetics
  • Endocytosis / drug effects
  • GTPase-Activating Proteins / antagonists & inhibitors
  • GTPase-Activating Proteins / genetics
  • GTPase-Activating Proteins / metabolism*
  • Glutathione / metabolism*
  • Humans
  • Lipid Peroxidation
  • Neoplasms / genetics
  • Neoplasms / metabolism
  • Neoplasms / pathology
  • Radiation Protection
  • Signal Transduction

Substances

  • ATP-Binding Cassette Transporters
  • GTPase-Activating Proteins
  • RALBP1 protein, human
  • Glutathione
  • Acetylcysteine