title: Elimination of hepatic metastases of colon cancer cells via p53-independent cross-talk between irinotecan and Apo2 ligand/TRAIL.
abstract: The majority of colorectal cancers have lost/inactivated the p53 tumor suppressor gene. Using isogenic human colon cancer cells that differ only in their p53 status, we demonstrate that loss of p53 renders tumor cells relatively resistant to the topoisomerase I inhibitor, irinotecan. Whereas irinotecan-induced up-regulation of the proapoptotic proteins PUMA and Noxa requires p53, we find that irinotecan inhibits Janus kinase 2 (JAK2)-signal transducer and activator of transcription 3 and 5 (STAT3/5) signaling in both p53-proficient and p53-deficient tumor cells. We show that irinotecan inhibits JAK2-STAT3/5-dependent expression of survival proteins (Bcl-x(L) and XIAP) and cooperates with Apo2 ligand/tumor necrosis factor-related apoptosis-inducing ligand (Apo2L/TRAIL) to facilitate p53-independent apoptosis of colon cancer cells. Whereas xenografts of p53-deficient colon cancer cells are relatively resistant to irinotecan compared with their p53-proficient counterparts, combined treatment with irinotecan and Apo2L/TRAIL eliminates hepatic metastases of both p53-proficient and p53-deficient cancer cells in vivo and significantly improves the survival of animals relative to treatment with either agent alone. Although the synergy between chemotherapy and Apo2L/TRAIL has been ascribed to p53, our data demonstrate that irinotecan enhances Apo2L/TRAIL-induced apoptosis of tumor cells via a distinct p53-independent mechanism involving inhibition of JAK2-STAT3/5 signaling. These findings identify a novel p53-independent channel of cross-talk between topoisomerase I inhibitors and Apo2L/TRAIL and suggest that the addition of Apo2L/TRAIL can improve the therapeutic index of irinotecan against both p53-proficient and p53-deficient colorectal cancers, including those that have metastasized to the liver.
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Rajani
authors.initials: R
authors.lastname: Ravi
authors.forename: Ajay J
authors.initials: AJ
authors.lastname: Jain
authors.forename: Richard D
authors.initials: RD
authors.lastname: Schulick
authors.forename: Vui
authors.initials: V
authors.lastname: Pham
authors.forename: Traci S
authors.initials: TS
authors.lastname: Prouser
authors.forename: Heather
authors.initials: H
authors.lastname: Allen
authors.forename: Elizabeth Garrett
authors.initials: EG
authors.lastname: Mayer
authors.forename: Hua
authors.initials: H
authors.lastname: Yu
authors.forename: Drew M
authors.initials: DM
authors.lastname: Pardoll
authors.forename: Avi
authors.initials: A
authors.lastname: Ashkenazi
authors.forename: Atul
authors.initials: A
authors.lastname: Bedi
mesh_terms: D000230:Adenocarcinoma / Q000473:pathology / Q000556:secondary; D000818:Animals; 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*; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004357:Drug Synergism; D005260:Female; D045325:HCT116 Cells; D006801:Humans; D000077146:Irinotecan; D053614:Janus Kinase 2; D008113:Liver Neoplasms / Q000188:drug therapy / Q000556:secondary*; D008562:Membrane Glycoproteins / Q000008:administration & dosage / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011506:Proteins / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D053221:TNF-Related Apoptosis-Inducing Ligand; D059004:Topoisomerase I Inhibitors; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000502:physiology; D051636:X-Linked Inhibitor of Apoptosis Protein; D023041:Xenograft Model Antitumor Assays; D051020:bcl-X Protein
chemical_list: D051017:Apoptosis Regulatory Proteins; C494811:BCL2L1 protein, human; C494812:Bcl2l1 protein, mouse; D008562:Membrane Glycoproteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; C505654:Tnfsf10 protein, mouse; D059004:Topoisomerase I Inhibitors; D014409:Tumor Necrosis Factor-alpha; D016159:Tumor Suppressor Protein p53; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D051020:bcl-X Protein; D000077146:Irinotecan; D011505:Protein-Tyrosine Kinases; C507924:JAK2 protein, human; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2; D002166:Camptothecin