RLIP76 Targeted Therapy for Kidney Cancer

Abstract

Despite recent improvements in chemotherapeutic approaches to treating kidney cancer, this malignancy remains deadly if not found and removed at an early stage of the disease. Kidney cancer is highly drug-resistant, which may at least partially result from high expression of transporter proteins in the cell membranes of kidney cells. Although these transporter proteins can contribute to drug-resistance, targeting proteins from the ATP-binding cassette transporter family has not been effective in reversing drug-resistance in kidney cancer. Recent studies have identified RLIP76 as a key stress-defense protein that protects normal cells from damage caused by stress conditions, including heat, ultra-violet light, X-irradiation, and oxidant/electrophilic toxic chemicals, and is crucial for protecting cancer cells from apoptosis. RLIP76 is the predominant glutathione-electrophile-conjugate (GS-E) transporter in cells, and inhibiting it with antibodies or through siRNA or antisense causes apoptosis in many cancer cell types. To date, blocking of RLIP76, either alone or in combination with chemotherapeutic drugs, as a therapeutic strategy for kidney cancer has not yet been evaluated in human clinical trials, although there is considerable potential for RLIP76 to be developed as a therapeutic agent for kidney cancer. In the present review, we discuss the mechanisms underlying apoptosis caused by RLIP76 depletion, the role of RLIP76 in clathrin-dependent endocytosis deficiency, and the feasibility of RLIP76-targeted therapy for kidney cancer.

Keywords: RLIP76; chemotherapeutics; drug-resistance; glutathione-conjugate transport; kidney cancer.

Figure 1. Schematic representation of RLIP76 domains

RLIP76 is a 655 amino acid protein with ATP binding sites at residues 69 to 74 and 418 to 425. The membrane-binding domain is from residues 154 to 219. The NH₂ terminus has an AP2 binding domain. The middle domain has the Rho/Rac GAP function. RLIP76 plays a role in the linking of Ras and Ral. RLIP76 can also regulate signaling downstream of Ras to cJun through its GAP activity toward the Rac/Rho family GTPase. Termination of signaling is mediated by endocytosis of the receptor-ligand complex. We propose that the ATPase activity of RLIP76 plays a significant role in this process, possibly as an energy transducer, and that this ATPase activity is coupled with efflux of endogenous substrate allocrites, particularly GS-E. The Ral-binding domain and POB1/cdc2 binding domain are the first half and second half of the COOH terminus region, respectively. RLIP76 plays a key effector role in different signaling pathways though its GS-E transport activity.

Figure 2. Proposed model for RLIP76 function

A model for control of signaling by RLIP76 through regulation of cellular levels of HNE and its metabolites (GS-HNE and GS-DHN). RLIP76 is a transporter of glutathione-conjugates of carcinogenic electrophiles (GS-E) arising from xenobiotic compounds as well as endogenously generated electrophilic compounds, particularly metabolites of lipid-peroxidation of ω-6 fatty acids (linoleic, γ-linolenic, arachidonic). Excessive consumption of ω-6 fatty acids is known to be associated with an increased risk for cancer.