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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|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.