Linking stress-signaling, glutathione metabolism, signaling pathways and xenobiotic transporters
- 27 January 2007
- journal article
- review article
- Published by Springer Science and Business Media LLC in Cancer and Metastasis Reviews
- Vol. 26 (1), 59-69
- https://doi.org/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.Keywords
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