Regression of prostate cancer xenografts by RLIP76 depletion.
RLIP76 plays a central role in radiation and chemotherapy resistance through its activity as a multi-specific ATP-dependent transporter which is over-expressed in a number of types of cancers. RLIP76 appears to be necessary for cancer cell survival because both in vitro cell culture and in vivo animal tumor studies show that depletion or inhibition of RLIP76 causes selective toxicity in malignant cells. RLIP76 induces apoptosis in cancer cells through the accumulation of endogenously formed GS-E. The results of our in vivo studies demonstrate that administration of RLIP76 antibodies, siRNA or anti-sense to mice bearing xenografts of PC-3 prostate cancer cells leads to near complete regression of established subcutaneous xenografts with no apparent toxic effects. Since anti-RLIP76 IgG (which inhibit RLIP76-mediated transport), siRNA and antisense (which deplete RLIP76) showed similar tumor regressing activities, our results indicate that the inhibition of RLIP76 transport activity at the cell surface is sufficient for observed anti-tumor activity. These studies indicate that RLIP76 serves a key effector function for the survival of prostate cancer cells and that it is a valid target for cancer therapy.
Singhal
Sharad S
SS
Department of Molecular Biology and Immunology, University of North Texas Health Science Center, Fort Worth, TX 76107, USA. ssinghal@hsc.unt.edu
Roth
Cherice
C
Leake
Kathryn
K
Singhal
Jyotsana
J
Yadav
Sushma
S
Awasthi
Sanjay
S
D018528:ATP-Binding Cassette Transporters / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism*; D000818:Animals; D001693:Biological Transport, Active / Q000276:immunology; D002460:Cell Line; D045744:Cell Line, Tumor; D020690:GTPase-Activating Proteins / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D007279:Injections, Subcutaneous; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D020320:Oligoribonucleotides, Antisense / Q000008:administration & dosage; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000628:therapy*; D012074:Remission Induction / Q000379:methods; D023041:Xenograft Model Antitumor Assays / Q000379:methods
D018528:ATP-Binding Cassette Transporters; D020690:GTPase-Activating Proteins; D020320:Oligoribonucleotides, Antisense; C095637:RALBP1 protein, human