BACKGROUND AND AIMS: Pancreatic cancer is a very aggressive malignancy. Normal cells die through apoptosis when detached from extracellular matrix (ECM), but the role of ECM in cancer cell survival is poorly understood. Here, we determined the effects of ECM proteins on death responses and underlying signaling pathways in human pancreatic cancer cells. METHODS: We measured apoptosis and necrosis, caspase activation, and mitochondrial dysfunction in MIA PaCa-2 and PANC-1 pancreatic carcinoma cells both detached and attached to ECM proteins. RESULTS: Detachment of pancreatic cancer cells from ECM did not induce classic apoptosis, as it does in normal cells, but induced necrosis and apoptosis associated with secondary necrosis. It caused a pronounced mitochondrial depolarization and release of cytochrome c and Smac/DIABLO. However, as different from normal cells, cytochrome c release did not result in downstream caspase activation. Executioner caspases were activated in detached pancreatic cancer cells independent of cytochrome c. Laminin and fibronectin, but not collagen I, markedly increased pancreatic cancer cell survival by inhibiting both mitochondrial dysfunction (leading to inhibition of necrosis) and caspase activity (leading to decreased apoptotic DNA fragmentation). CONCLUSIONS: ECM proteins greatly protect pancreatic cancer cells from death by mechanisms different from those operating in normal cells. The results suggest ECM proteins and their receptors as potential targets for treatment of pancreatic cancer.
BACKGROUND AND AIMS: Pancreatic cancer is a very aggressive malignancy. Normal cells die through apoptosis when detached from extracellular matrix (ECM), but the role of ECM in cancer cell survival is poorly understood. Here, we determined the effects of ECM proteins on death responses and underlying signaling pathways in humanpancreatic cancer cells. METHODS: We measured apoptosis and necrosis, caspase activation, and mitochondrial dysfunction in MIA PaCa-2 and PANC-1 pancreatic carcinoma cells both detached and attached to ECM proteins. RESULTS: Detachment of pancreatic cancer cells from ECM did not induce classic apoptosis, as it does in normal cells, but induced necrosis and apoptosis associated with secondary necrosis. It caused a pronounced mitochondrial depolarization and release of cytochrome c and Smac/DIABLO. However, as different from normal cells, cytochrome c release did not result in downstream caspase activation. Executioner caspases were activated in detached pancreatic cancer cells independent of cytochrome c. Laminin and fibronectin, but not collagen I, markedly increased pancreatic cancer cell survival by inhibiting both mitochondrial dysfunction (leading to inhibition of necrosis) and caspase activity (leading to decreased apoptotic DNA fragmentation). CONCLUSIONS: ECM proteins greatly protect pancreatic cancer cells from death by mechanisms different from those operating in normal cells. The results suggest ECM proteins and their receptors as potential targets for treatment of pancreatic cancer.
Authors: Claudia Nitsche; Mouad Edderkaoui; Ryan M Moore; Guido Eibl; Noriyuki Kasahara; Janet Treger; Paul J Grippo; Julia Mayerle; Markus M Lerch; Anna S Gukovskaya Journal: Gastroenterology Date: 2011-10-29 Impact factor: 22.682
Authors: Guido Eibl; Zobeida Cruz-Monserrate; Murray Korc; Maxim S Petrov; Mark O Goodarzi; William E Fisher; Aida Habtezion; Aurelia Lugea; Stephen J Pandol; Phil A Hart; Dana K Andersen Journal: J Acad Nutr Diet Date: 2017-09-12 Impact factor: 4.910
Authors: Paul A Toste; Andrew H Nguyen; Brian E Kadera; Mindy Duong; Nanping Wu; Irmina Gawlas; Linh M Tran; Mihir Bikhchandani; Luyi Li; Sanjeet G Patel; David W Dawson; Timothy R Donahue Journal: Mol Cancer Res Date: 2016-03-15 Impact factor: 5.852
Authors: Izumi Ohno; Guido Eibl; Irina Odinokova; Mouad Edderkaoui; Robert D Damoiseaux; Moussa Yazbec; Ravinder Abrol; William A Goddard; Osamu Yokosuka; Stephen J Pandol; Anna S Gukovskaya Journal: Am J Physiol Gastrointest Liver Physiol Date: 2009-09-17 Impact factor: 4.052