title: 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.
authors.affiliation: Department of Diabetes & Metabolic Diseases Research, City of Hope, Comprehensive Cancer Center, Duarte, California, 91010, USA. ssinghal@coh.org.
authors.forename: Sharad S
authors.initials: SS
authors.lastname: Singhal
authors.affiliation: Department of Diabetes & Metabolic Diseases Research, City of Hope, Comprehensive Cancer Center, Duarte, California, 91010, USA.
authors.forename: Jyotsana
authors.initials: J
authors.lastname: Singhal
authors.affiliation: Department of Diabetes & Metabolic Diseases Research, City of Hope, Comprehensive Cancer Center, Duarte, California, 91010, USA.
authors.forename: James
authors.initials: J
authors.lastname: Figarola
authors.affiliation: Department of Molecular Medicine, City of Hope, Comprehensive Cancer Center, Duarte, California, 91010, USA.
authors.forename: David
authors.initials: D
authors.lastname: Horne
authors.affiliation: Department of Diabetes & Metabolic Diseases Research, City of Hope, Comprehensive Cancer Center, Duarte, California, 91010, USA.|Department of Medical Oncology, Beckman Research Institute, City of Hope, Comprehensive Cancer Center, Duarte, California, 91010, USA.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Awasthi
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004705:Endocytosis / Q000502:physiology; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000378:metabolism
chemical_list: D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D005978:Glutathione
keywords: RLIP76; chemotherapeutics; drug-resistance; glutathione-conjugate transport; kidney cancer