Par‐4 dependent modulation of cellular β‐catenin by medicinal plant natural product derivative 3‐azido Withaferin A

This study, for the first time, reveals 3‐AWA treatment consistently sequestered nuclear β‐catenin and augmented its cytoplasmic pool as evidenced by reducing β‐catenin transcriptional activity in these cells. Moreover, 3‐AWA treatment triggered robust induction of pro‐apoptotic intracellular Par‐4, attenuated Akt activity and rescued Phospho‐GSK3β (by Akt) to promote β‐catenin destabilization. Further, our in vitro studies demonstrate that 3‐AWA treatment amplified E‐cadherin expression along with sharp downregulation of c‐Myc and cyclin D1 proteins. Strikingly, endogenous Par‐4 knock down by siRNA underscored 3‐AWA mediated inhibition of nuclear β‐catenin was Par‐4 dependent and suppression of Par‐4 activity, either by Bcl‐2 or by Ras transfection, restored the nuclear β‐catenin level suggesting Par‐4 mediated β‐catenin regulation was not promiscuous. In vivo results further demonstrated that 3‐AWA was effective inhibitor of tumor growth and immunohistochemical studies indicated that increased expression of total β‐catenin and decreased expression of phospho‐β‐catenin and Par‐4 in breast cancer tissues as compared to normal breast tissue suggesting Par‐4 and β‐catenin proteins are mutually regulated and inversely co‐related in normal as well as cancer condition. Thus, strategic regulation of intracellular Par‐4 by 3‐AWA in diverse cancers could be an effective tool to control cancer cell metastasis. Concl...
Source: Molecular Carcinogenesis - Category: Molecular Biology Authors: Tags: Research Article Source Type: research