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

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.

Self-regulatory role of 4-hydroxynonenal in signaling for stress-induced programmed cell death

“…The role of the HNE in transducing the membrane receptor-mediated signaling is further confirmed by our recent studies in which we show that the overexpression of RalBP1 in response to the increased level of HNE leads to increased endocytosis of the EGF receptor. RalBP1 along with the POB1 (partner of RalBP1) has been shown to be present in signal transduction complexes for membrane tyrosine-kinase receptors (such as EGF-R) and are phosphorylated [113][114][115][116]. The inhibition of endocytosis in the transport-deficient mutants of RalBP1 further supports the idea that the transport and endocytotic functions of RalBP1 are regulated by the cellular concentration of HNE and HNE-SG.…”

“…when coated with RalBP1 antibodies to block the transport of the GSH conjugates of HNE or its metabolites. The inhibition of the transport functions of RalBP1 by RalBP1-interacting proteins, POB1 and HSF1, also leads to apoptosis of cancer cells, further supporting the role of HNE and HNE-SG as regulatory signals for various cellular processes [113,116].…”

“…GSTs catalyze the conjugation of HNE to glutathione (GSH) which is the major pathway for disposition of HNE. The glutathione conjugate of HNE (GS-HNE) can be further acted on by aldehyde dehydrogenase or aldose reductase to yield corresponding acid and alcohol, respectively, but the majority of GS-HNE is transported by RalBP1 for excretion or its further processing to mercapturic acids [11,12,113]. Blocking of the transport of GS-HNE leads to the buildup of GS-HNE and HNE levels in cells as demonstrated in vitro in cell cultures, as well as in vivo in mGSTA4 knockout and RalBP1 knockout mice.…”

Novel Flavonoid Didymin Inhibits Neuroblastomas—Response

“…The reactive oxygen species (ROS) stimulate the activation of critical signaling pathways including mitogen-activated protein kinase (MAPK) pathway (5). The modulation of ROS can lead to a plethora of effects on cellular proliferation and apoptosis (6). Indeed, as part of follow-up studies, we are seeking to address the role of ROS in mediating the effects of didymin in neuroblastomas.…”

Role of RLIP76 in doxorubicin resistance in lung cancer (Review)

“…It has Nmyristolation sites at amino acid 21-26, 40-45, and 191-196. There are vector peptide-related sequences between amino acid 154 and 219 including the penetratin-like sequence 154 LTAADVVKQWKEKKKKK 170 , a TAT-like sequence from amino acid 170-185, and a hydrophobic stretch from amino acid 203-219. Both membrane association and transport requires this domain (8,20,21). Two central domains include, one carrying a Rac/cdc42 GAP (through aa 210-357) activity, while the other binds to activated Ral (aa 391-499).…”