GSK-3β regulated NFATc1 transcription complexes in pancreatic carcinogenesis and drug resistance
Summary:
A better understanding of the molecular carcinogenesis and in particular of mechanisms that convey resistance to conventional
cytotoxic therapy is urgently needed to develop more effective therapeutic strategies to defend pancreatic cancer. Growing
evidence suggests that mutational activation of oncogenic K-Ras initiates pancreatic carcinogenesis but requires additional
genetic, epigenetic and signaling events to overcome cellular defense mechanisms and promote premalignant lesions towards
invasively growing cancers. One such critical event is the ectopic induction and activation of NFAT transcription factors which
control key aspects of carcinogenesis through their ability to integrate signals from other transcription pathways into specific
gene responses. In the first funding period we focused on signaling regulation of NFAT factors in pancreatic cancer and identified
the serine/threonine kinase GSK-3β as a master regulator of NFAT stability and transcription. GSK-3β targets nuclear NFAT
factors for phosphorylation dependent stabilization in pancreatic cancer cells and in addition, promotes complex formation with the
oncogenic transcription factors NF-ĸB and Signal transducer and activator of transcription 3 (STAT3). In the next funding period, we
take advantage of genetic engineered mice (P48+/Cre; LSL-KrasG12D/+; NFATc1 (NKC mice)) with pancreas specific
expression of KrasG12D and NFATc1. This transgenic mice model recapitulates the human disease and develops stepwise
transformation of exocrine pancreatic epithelium to preinvasive precursor lesions and invasively growing cancers. We will employ
this tumor model and primary cell lines to comprehensively characterize the mechanisms, function and GSK-3β dependent regulation
of NFAT-(NF-ĸB/STAT3) complex formation in gene transcription during pancreatic carcinogenesis and drug resistance.