%0 Journal Article
%T Par-4 mediated Smad4 induction in PDAC cells restores canonical TGF-β/ Smad4 axis driving the cells towards lethal EMT.
%A Mohd Faheem M
%A Rasool RU
%A Ahmad SM
%A Jamwal VL
%A Chakraborty S
%A Katoch A
%A Gandhi SG
%A Bhagat M
%A Goswami A
%J Eur J Cell Biol
%V 99
%N 4
%D May 2020
%M 32439219
%F 6.02
%R 10.1016/j.ejcb.2020.151076
%X Deregulation of TGF-β signaling is intricately engrossed in the pathophysiology of pancreatic adenocarcinomas (PDACs). The role of TGF-β all through pancreatic cancer initiation and progression is multifarious and somewhat paradoxical. TGF-β plays a tumor suppressive role in early-stage pancreatic cancer by promoting apoptosis and inhibiting epithelial cell cycle progression, but incites tumor promotion in late-stage by modulating genomic instability, neo-angiogenesis, immune evasion, cell motility, and metastasis. Here, we provide evidences that Par-4 acts as one of the vital mediators to regulate TGF-β/Smad4 pathway, wherein, Par-4 induction/over-expression induced EMT which was later culminated in to apoptosis in presence of TGF-β via positive regulation of Smad4. Intriguingly, Par-4-/- cells were devoid of significant Smad4 induction compared to Par-4+/+ cells in presence of TGF-β and ectopic Par-4 steadily augmented Smad4 expression by restoring TGF-β/Smad4 axis in Panc-1 cells. Further, our FACS and western blotting results unveiled that Par-4 dragged the PDAC cells to G1 arrest in presence of TGF-β byelevating p21 and p27 levels while attenuating Cyclin E and A levels and augmenting caspase 3 cleavage triggering lethal EMT. Through restoration of Smad4, we further establish that in BxPC3 cell line (Smad4-/-), Smad4 is essential for Par-4 to indulge TGF-β dependent lethal EMT program. The mechanistic relevance of Par-4 mediated Smad4 activation was additionally validated by co-immunoprecipitation wherein disruption of NM23H1-STRAP interaction by Par-4 rescues TGF-β/Smad4 pathway in PDAC and mediates the tumor suppressive role of TGF-β, therefore serving as a vital cog to restore the apoptotic functions of TGF-β pathway.