Abstract
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.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adenine Nucleotides / administration & dosage
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Adenine Nucleotides / pharmacology
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Antineoplastic Combined Chemotherapy Protocols / pharmacology*
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Apoptosis / drug effects*
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Apoptosis / physiology
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Apoptosis Regulatory Proteins
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Camptothecin / administration & dosage
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Camptothecin / analogs & derivatives*
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Camptothecin / pharmacology
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Drug Synergism
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Endoribonucleases / deficiency
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Endoribonucleases / genetics
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Endoribonucleases / metabolism*
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Enzyme Inhibitors / administration & dosage
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Enzyme Inhibitors / pharmacology
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Humans
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Irinotecan
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JNK Mitogen-Activated Protein Kinases / antagonists & inhibitors
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JNK Mitogen-Activated Protein Kinases / metabolism
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MAP Kinase Kinase 4
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Male
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Membrane Glycoproteins / administration & dosage
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Membrane Glycoproteins / pharmacology
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Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors
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Mitogen-Activated Protein Kinase Kinases / metabolism
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Oligoribonucleotides / administration & dosage
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Oligoribonucleotides / pharmacology
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Prostatic Neoplasms / drug therapy*
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Prostatic Neoplasms / genetics
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Prostatic Neoplasms / pathology
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TNF-Related Apoptosis-Inducing Ligand
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Topoisomerase I Inhibitors*
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Topotecan / administration & dosage
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Topotecan / pharmacology
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Transfection
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Tumor Necrosis Factor-alpha / administration & dosage
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Tumor Necrosis Factor-alpha / pharmacology
Substances
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Adenine Nucleotides
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Apoptosis Regulatory Proteins
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Enzyme Inhibitors
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Membrane Glycoproteins
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Oligoribonucleotides
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TNF-Related Apoptosis-Inducing Ligand
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TNFSF10 protein, human
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Topoisomerase I Inhibitors
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Tumor Necrosis Factor-alpha
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2',5'-oligoadenylate
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Irinotecan
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Topotecan
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JNK Mitogen-Activated Protein Kinases
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MAP Kinase Kinase 4
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Mitogen-Activated Protein Kinase Kinases
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Endoribonucleases
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2-5A-dependent ribonuclease
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Camptothecin