Elimination of Hepatic Metastases of Colon Cancer Cells via p53-Independent Cross-Talk between Irinotecan and Apo2 Ligand/TRAIL

摘要: The majority of colorectal cancers have lost/inactivated the p53 tumor suppressor gene. Using isogenic human colon cancer cells that differ only in their status, we demonstrate loss renders relatively resistant to topoisomerase I inhibitor, irinotecan. Whereas irinotecan-induced up-regulation proapoptotic proteins PUMA and Noxa requires p53, find irinotecan inhibits Janus kinase 2 (JAK2)-signal transducer activator transcription 3 5 (STAT3/5) signaling both p53-proficient p53-deficient cells. We show JAK2-STAT3/5-dependent expression survival (Bcl-xL XIAP) cooperates with Apo2 ligand/tumor necrosis factor-related apoptosis-inducing ligand (Apo2L/TRAIL) facilitate p53-independent apoptosis xenografts are compared counterparts, combined treatment Apo2L/TRAIL eliminates hepatic metastases vivo significantly improves animals relative either agent alone. Although synergy between chemotherapy has been ascribed our data enhances Apo2L/TRAIL-induced via a distinct mechanism involving inhibition JAK2-STAT3/5 signaling. These findings identify novel channel cross-talk inhibitors suggest addition can improve therapeutic index against cancers, including those metastasized liver.