The Non-ABC Drug Transporter RLIP76 (RALBP-1) Plays a Major Role in the Mechanisms of Drug Resistance

Title: The Non-ABC Drug Transporter RLIP76 (RALBP-1) Plays a Major Role in the Mechanisms of Drug Resistance

Volume: 8 Issue: 4

Author(s): Yogesh C. Awasthi, Rajendra Sharma, Sushma Yadav, Seema Dwivedi, Abha Sharma and Sanjay Awasthi

Affiliation:

Keywords: ABCG transporters, oxidized GSH, Proteoliposomes, Stress Response, Cell cycle regulatory protein

Abstract: 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.

Cite this article as:

Awasthi C. Yogesh, Sharma Rajendra, Yadav Sushma, Dwivedi Seema, Sharma Abha and Awasthi Sanjay, The Non-ABC Drug Transporter RLIP76 (RALBP-1) Plays a Major Role in the Mechanisms of Drug Resistance, Current Drug Metabolism 2007; 8 (4) . https://dx.doi.org/10.2174/138920007780655414