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

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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.

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  1. Department of Chemistry and Biochemistry, University of Texas at Arlington, 700 Planetarium Place, CPB Room # 312, Arlington, TX, 76019-0065, USA

    Sushma Yadav, Ewa Zajac, Sharad S. Singhal & Sanjay Awasthi

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  1. Sushma Yadav
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  2. Ewa Zajac
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  3. Sharad S. Singhal
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  4. Sanjay Awasthi
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Correspondence to Sanjay Awasthi.

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Yadav, S., Zajac, E., Singhal, S.S. et al. Linking stress-signaling, glutathione metabolism, signaling pathways and xenobiotic transporters. Cancer Metastasis Rev 26, 59–69 (2007). https://doi.org/10.1007/s10555-007-9043-5

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