The non-ABC drug transporter RLIP76 (RALBP-1) plays a major role in the mechanisms of drug resistance.
RLIP76 or Ral binding protein (RalBP-1) was initially cloned as a Ral-effector that was proposed as a link between Ral and Ras pathways. This protein is encoded in humans on chromosome 18p11.3 by a gene with 11 exons and 9 introns and is found ubiquitously from drosophila to humans. RLIP76 displays inhibitory GTPase activity toward Rho/Rac class G-protein cdc42 which is involved in regulation of cytoskeletal organization, lamellipodia, cell migration and apoptosis via Ras. We have recently shown that RLIP76 is also a multispecific transporter of chemotherapeutic agents and glutathione conjugates (GS-E). In human cells RLIP76 accounts for more than two third of the transport activity for GS-E and drugs as opposed to the ABC-transporters including MRP1, which account for less than one third of this activity. Evidence is mounting that RLIP76 is a stress-responsive multi-specific, non-ABC transporter which represents an entirely novel link between stress-inducible G-protein signaling, receptor tyrosine-kinase signaling, endocytosis, heat-shock and stress defense pathways, and transport mediated drug-resistance. The expression of RLIP76 is significantly greater in human cancer cells of diverse origin as compared to the non-malignant cells. Inhibition of RLIP76, using antibodies towards a cell surface epitope, or depletion of RLIP76 using either siRNA or anti-sense phosphorothioate oligonucleotides preferentially causes apoptosis in malignant cells. Administration of RLIP76 antibodies, siRNA, or anti-sense oligonucleotides to mice bearing syngeneic B16 mouse melanoma tumors causes rapid and complete regression of tumors. Studies summarized in this review strongly suggest that RLIP76 is a logical target for clinical intervention of not only multi-drug resistance but also for diseases resulting from oxidative stress.
Awasthi
Yogesh C
YC
Department of Biochemistry and Molecular Biology, 551-Basic Science Bldg., University of Texas Medical Branch at Galveston, Galveston, TX 77555-0647, USA. ycawasth@utmb.edu
Sharma
Rajendra
R
Yadav
Sushma
S
Dwivedi
Seema
S
Sharma
Abha
A
Awasthi
Sanjay
S
D018528:ATP-Binding Cassette Transporters / Q000737:chemistry / Q000378:metabolism*; D000251:Adenosine Triphosphatases / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism; D017209:Apoptosis; D018797:Cell Cycle Proteins / Q000378:metabolism; D004351:Drug Resistance; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D020690:GTPase-Activating Proteins / Q000737:chemistry / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism*; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology; D011487:Protein Conformation; D011493:Protein Kinase C / Q000378:metabolism; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D018528:ATP-Binding Cassette Transporters; D000251:Adenosine Triphosphatases; D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D020690:GTPase-Activating Proteins; D005978:Glutathione; D006360:Heat-Shock Proteins; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011493:Protein Kinase C; D016159:Tumor Suppressor Protein p53; C095637:RALBP1 protein, human; C490620:Ralbp1 protein, mouse; C068387:S-(dinitrophenyl)glutathione ATPase; C421109:multidrug resistance-associated protein 1