title: Par-4 dependent modulation of cellular β-catenin by medicinal plant natural product derivative 3-azido Withaferin A.
abstract: Here, we provide evidences that natural product derivative 3-azido Withaferin A (3-AWA) abrogated EMT and invasion by modulating β-catenin localization and its transcriptional activity in the prostate as well as in breast cancer cells. 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. Conclusively, this report puts forward a novel approach of controlling deregulated β-catenin signaling by 3-AWA induced Par-4 protein.
authors.affiliation: Cancer Pharmacology Division, Indian Institute of Integrative Medicine (CSIR), Canal Road, Jammu Tawi, Jammu and Kashmir, India.|School of Biosciences and Biotechnology, Baba Ghulam Shah Badshah University, Rajouri, Jammu and Kashmir, India.
authors.forename: Hina
authors.initials: H
authors.lastname: Amin
authors.affiliation: Cancer Pharmacology Division, Indian Institute of Integrative Medicine (CSIR), Canal Road, Jammu Tawi, Jammu and Kashmir, India.
authors.forename: Debasis
authors.initials: D
authors.lastname: Nayak
authors.affiliation: Cancer Pharmacology Division, Indian Institute of Integrative Medicine (CSIR), Canal Road, Jammu Tawi, Jammu and Kashmir, India.
authors.forename: Reyaz
authors.initials: R
authors.lastname: Ur Rasool
authors.affiliation: Cancer Pharmacology Division, Indian Institute of Integrative Medicine (CSIR), Canal Road, Jammu Tawi, Jammu and Kashmir, India.
authors.forename: Souneek
authors.initials: S
authors.lastname: Chakraborty
authors.affiliation: Center for Cellular and Molecular Biology, Uppal Road, Hyderabad, Andra Pradesh, India.
authors.forename: Anmol
authors.initials: A
authors.lastname: Kumar
authors.affiliation: Natural Product Chemistry, Indian Institute of Integrative Medicine (CSIR), Canal Road, Jammu Tawi, Jammu and Kashmir, India.
authors.forename: Khalid
authors.initials: K
authors.lastname: Yousuf
authors.affiliation: Cancer Pharmacology Division, Indian Institute of Integrative Medicine (CSIR), Canal Road, Jammu Tawi, Jammu and Kashmir, India.
authors.forename: Parduman Raj
authors.initials: PR
authors.lastname: Sharma
authors.affiliation: Cancer Pharmacology Division, Indian Institute of Integrative Medicine (CSIR), Canal Road, Jammu Tawi, Jammu and Kashmir, India.
authors.forename: Zabeer
authors.initials: Z
authors.lastname: Ahmed
authors.affiliation: Cancer Pharmacology Division, Indian Institute of Integrative Medicine (CSIR), Canal Road, Jammu Tawi, Jammu and Kashmir, India.
authors.forename: Neelam
authors.initials: N
authors.lastname: Sharma
authors.affiliation: Cancer Pharmacology Division, Indian Institute of Integrative Medicine (CSIR), Canal Road, Jammu Tawi, Jammu and Kashmir, India.
authors.forename: Asmita
authors.initials: A
authors.lastname: Magotra
authors.affiliation: Natural Product Chemistry, Indian Institute of Integrative Medicine (CSIR), Canal Road, Jammu Tawi, Jammu and Kashmir, India.
authors.forename: Debaraj
authors.initials: D
authors.lastname: Mukherjee
authors.affiliation: Center for Cellular and Molecular Biology, Uppal Road, Hyderabad, Andra Pradesh, India.
authors.forename: Lekha Dinesh
authors.initials: LD
authors.lastname: Kumar
authors.affiliation: Cancer Pharmacology Division, Indian Institute of Integrative Medicine (CSIR), Canal Road, Jammu Tawi, Jammu and Kashmir, India.
authors.forename: Anindya
authors.initials: A
authors.lastname: Goswami
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000494:pharmacology; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D010946:Plants, Medicinal / Q000737:chemistry; D015398:Signal Transduction / Q000187:drug effects; D054358:Withanolides / Q000819:agonists*; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D051017:Apoptosis Regulatory Proteins; C495270:CTNNB1 protein, human; D054358:Withanolides; D051176:beta Catenin; C101296:prostate apoptosis response-4 protein; C009684:withaferin A
keywords: EMT; GSK3β; Par-4; metastasis; β-catenin