HPC1/RNASEL mediates apoptosis of prostate cancer cells treated with 2',5'-oligoadenylates, topoisomerase I inhibitors, and tumor necrosis factor-related apoptosis-inducing ligand.
The hereditary prostate cancer 1 (HPC1) allele maps to the RNASEL gene encoding a protein (RNase L) implicated in the antiviral activity of interferons. To investigate the possible role of RNase L in apoptosis of prostate cancer cells, we decreased levels of RNase L by severalfold in the DU145 human prostate cancer cell line through the stable expression of a small interfering RNA (siRNA). Control cells expressed siRNA with three mismatched nucleotides to the RNase L sequence. Cells deficient in RNase L, but not the control cells, were highly resistant to apoptosis by the RNase L activator, 2',5'-oligoadenylate (2-5A). Surprisingly, the RNase L-deficient cells were also highly resistant to apoptosis by combination treatments with a topoisomerase (Topo) I inhibitor (camptothecin, topotecan, or SN-38) and tumor necrosis factor-related apoptosis-inducing ligand [TRAIL (Apo2L)]. In contrast, cells expressing siRNA to the RNase L inhibitor RLI (HP68) showed enhanced apoptosis in response to Topo I inhibitor alone or in combination with TRAIL. An inhibitor of c-Jun NH(2)-terminal kinases reduced apoptosis induced by treatment with either 2-5A or the combination of camptothecin and TRAIL, thus implicating c-Jun NH(2)-terminal kinase in the apoptotic signaling pathway. Furthermore, prostate cancer cells were sensitive to apoptosis from the combination of 2-5A with either TRAIL or Topo I inhibitor, whereas normal prostate epithelial cells were partially resistant to apoptosis. These findings indicate that RNase L integrates and amplifies apoptotic signals generated during treatment of prostate cancer cells with 2-5A, Topo I inhibitors, and TRAIL.
Malathi
Krishnamurthy
K
Department of Cancer Biology, Lerner Research Institute, and Experimental Therapeutics Program, Taussig Cancer Center, The Cleveland Clinic Foundation, Cleveland, Ohio, USA.
Paranjape
Jayashree M
JM
Ganapathi
Ram
R
Silverman
Robert H
RH
D000227:Adenine Nucleotides / Q000008:administration & dosage / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D051017:Apoptosis Regulatory Proteins; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D004357:Drug Synergism; D004722:Endoribonucleases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D006801:Humans; D000077146:Irinotecan; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D048670:MAP Kinase Kinase 4; D008297:Male; D008562:Membrane Glycoproteins / Q000008:administration & dosage / Q000494:pharmacology; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009843:Oligoribonucleotides / Q000008:administration & dosage / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D053221:TNF-Related Apoptosis-Inducing Ligand; D059004:Topoisomerase I Inhibitors; D019772:Topotecan / Q000008:administration & dosage / Q000494:pharmacology; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000494:pharmacology
D000227:Adenine Nucleotides; D051017:Apoptosis Regulatory Proteins; D004791:Enzyme Inhibitors; D008562:Membrane Glycoproteins; D009843:Oligoribonucleotides; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D059004:Topoisomerase I Inhibitors; D014409:Tumor Necrosis Factor-alpha; C023505:2',5'-oligoadenylate; D000077146:Irinotecan; D019772:Topotecan; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases; D004722:Endoribonucleases; C031956:2-5A-dependent ribonuclease; D002166:Camptothecin