Molecular characterization of TGF-β mediated cancer cell proliferation
TGF-β inhibits epithelial cell growth through Smad-dependent induction of a cell cycle arrest at G1. During tumor progression, however, many tumor cells escape from TGF-β growth suppression due to either functional or genetic disruption of the Smad signaling pathway. In late tumor stages, TGF-β s...
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|Zusammenfassung:||TGF-β inhibits epithelial cell growth through Smad-dependent induction of a cell cycle arrest at G1. During tumor progression, however, many tumor cells escape from TGF-β growth suppression due to either functional or genetic disruption of the Smad signaling pathway. In late tumor stages, TGF-β stimulates tumor cell proliferation through increased cell cycle transition. Although this cellular event is clearly established, the molecular mechanisms underlying this phenomenon remain unknown. Here, we show that TGF-β stimulation induces cancer cell proliferation via accelerated G1/S phase transition. We show that cell proliferation requires induction of the c-Myc oncogene, and this is paralleled by upregulation of D-type cyclins and their corresponding CdKs. TGF-β induces c-Myc expression on the level of promoter regulation through induction of the c-Myc/TIE element, which has previously been reported as the core element for repression of c-Myc in growth inhibited cells. Mechanistically, TGF-β induces c-Myc promoter activation through the calcium responsive NFAT transcription factor family. We show that TGF-β induces expression and subsequent nuclear accumulation of NFATc1 and NFATc2 in cancer cells. NFAT proteins then bind to and displace Smad repressor complexes from the c-Myc/TIE to induce the c-Myc promoter transactivation and expression. c-Myc induction, on the other hand, is essential for subsequent cyclin upregulation and stimulation of G1/S phase transition in cancer. Thus, this study uncovers a key signaling and transcription pathway in TGF-β growth stimulation and identifies the NFAT transcription factor family as essential mediators of this function. From the medical point of view this study not only help to better understand the mechanisms underlying TGF-β growth promotion in cancer, but also provide a platform for novel options in the treatment of pancreatic cancer. In fact, recent approaches led to the identification of novel and interesting molecules that target the NFAT pathway more specifically in tumor cells. Future studies will show whether specific targeting of the NFAT system in tumor cells is a promising new strategy in the treatment of pancreatic cancer and in particular in those with high levels of TGF-β.|