Oncotarget

Research Papers:

Withaferin-A suppress AKT induced tumor growth in colorectal cancer cells

Suman Suman, Trinath P. Das, Suman Sirimulla, Houda Alatassi, Murali K. Ankem, Chendil Damodaran _

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Oncotarget. 2016; 7:13854-13864. https://doi.org/10.18632/oncotarget.7351

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Abstract

Suman Suman1, Trinath P. Das1, Suman Sirimulla2, Houda Alatassi3, Murali K. Ankem1, Chendil Damodaran1

1Department of Urology, University of Louisville, Louisville, KY 40202, USA

2Department of Basic Sciences, St. Louis College of Pharmacy, St. Louis, MO 63110, USA

3Department of Pathology, University of Louisville, Louisville, KY 40202, USA

Correspondence to:

Chendil Damodaran, e-mail: chendil.damodaran@louisville.edu

Keywords: tumor growth, EMT, chemoprevention, natural compound, proliferation

Received: November 11, 2015     Accepted: January 29, 2016     Published: February 12, 2016

ABSTRACT

The oncogenic activation of AKT gene has emerged as a key determinant of the aggressiveness of colorectal cancer (CRC); hence, research has focused on targeting AKT signaling for the treatment of advanced stages of CRC. In this study, we explored the anti-tumorigenic effects of withaferin A (WA) on CRC cells overexpressing AKT in preclinical (in vitro and in vivo) models. Our results indicated that WA, a natural compound, resulted in significant inhibition of AKT activity and led to the inhibition of cell proliferation, migration and invasion by downregulating the epithelial to mesenchymal transition (EMT) markers in CRC cells overexpressing AKT. The oral administration of WA significantly suppressed AKT-induced aggressive tumor growth in a xenograft model. Molecular analysis revealed that the decreased expression of AKT and its downstream pro-survival signaling molecules may be responsible for tumor inhibition. Further, significant inhibition of some important EMT markers, i.e., Snail, Slug, β-catenin and vimentin, was observed in WA-treated human CRC cells overexpressing AKT. Significant inhibition of micro-vessel formation and the length of vessels were evident in WA-treated tumors, which correlated with a low expression of the angiogenic marker RETIC. In conclusion, the present study emphasizes the crucial role of AKT activation in inducing cell proliferation, angiogenesis and EMT in CRC cells and suggests that WA may overcome AKT-induced cell proliferation and tumor growth in CRC.


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