Linking stress-signaling, glutathione metabolism, signaling pathways and xenobiotic transporters.
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.
Yadav
Sushma
S
Department of Chemistry and Biochemistry, University of Texas at Arlington, TX 76019-0065, USA.
Zajac
Ewa
E
Singhal
Sharad S
SS
Awasthi
Sanjay
S
D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000111:Acetylcysteine / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004705:Endocytosis / Q000187:drug effects; D020690:GTPase-Activating Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism*; D006801:Humans; D015227:Lipid Peroxidation; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011835:Radiation Protection; D015398:Signal Transduction
D018528:ATP-Binding Cassette Transporters; D020690:GTPase-Activating Proteins; C095637:RALBP1 protein, human; D005978:Glutathione; D000111:Acetylcysteine