Oncotarget

Research Papers:

Apigenin blocks IKKα activation and suppresses prostate cancer progression

Sanjeev Shukla, Rajnee Kanwal, Eswar Shankar, Manish Datt, Mark R. Chance, Pingfu Fu, Gregory T. MacLennan, Sanjay Gupta _

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Oncotarget. 2015; 6:31216-31232. https://doi.org/10.18632/oncotarget.5157

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Abstract

Sanjeev Shukla1,2, Rajnee Kanwal1,2, Eswar Shankar1,2, Manish Datt3, Mark R. Chance3, Pingfu Fu4, Gregory T. MacLennan5, Sanjay Gupta1,2,6,7,8

1Department of Urology, Case Western Reserve University & University Hospitals Case Medical Center, Cleveland, Ohio 44106, USA

2The Urology Institute, University Hospitals Case Medical Center, Cleveland, Ohio 44106, USA

3Center for Proteomics and Bioinformatics, Case Western Reserve University, Cleveland, Ohio 44106, USA

4Department of Epidemiology & Biostatistics, Case Western Reserve University & University Hospitals Case Medical Center, Cleveland, Ohio 44106, USA

5Department of Pathology, Case Western Reserve University & University Hospitals Case Medical Center, Cleveland, Ohio 44106, USA

6Department of Nutrition, Case Western Reserve University & University Hospitals Case Medical Center, Cleveland, Ohio 44106, USA

7Divison of General Medical Sciences, Case Comprehensive Cancer Center, Cleveland, Ohio 44106, USA

8Department of Urology, Louis Stokes Cleveland Veterans Affairs Medical Center, Cleveland, Ohio 44106, USA

Correspondence to:

Sanjay Gupta, e-mail: sanjay.gupta@case.edu

Keywords: prostate cancer, apigenin, NF-ĸB signaling, therapeutic target, cell cycle

Received: May 19, 2015     Accepted: August 24, 2015     Published: September 05, 2015

ABSTRACT

IKKα has been implicated as a key regulator of oncogenesis and driver of the metastatic process; therefore is regarded as a promising therapeutic target in anticancer drug development. In spite of the progress made in the development of IKK inhibitors, no potent IKKα inhibitor(s) have been identified. Our multistep approach of molecular modeling and direct binding has led to the identification of plant flavone apigenin as a specific IKKα inhibitor. Here we report apigenin, in micro molar range, inhibits IKKα kinase activity, demonstrates anti-proliferative and anti-invasive activities in functional cell based assays and exhibits anticancer efficacy in experimental tumor model. We found that apigenin directly binds with IKKα, attenuates IKKα kinase activity and suppresses NF-ĸB/p65 activation in human prostate cancer PC-3 and 22Rv1 cells much more effectively than IKK inhibitor, PS1145. We also showed that apigenin caused cell cycle arrest similar to knockdown of IKKα in prostate cancer cells. Studies in xenograft mouse model indicate that apigenin feeding suppresses tumor growth, lowers proliferation and enhances apoptosis. These effects correlated with inhibition of p-IKKα, NF-ĸB/p65, proliferating cell nuclear antigen and increase in cleaved caspase 3 expression in a dose-dependent manner. Overall, our results suggest that inhibition of cell proliferation, invasiveness and decrease in tumor growth by apigenin are mediated by its ability to suppress IKKα and downstream targets affecting NF-ĸB signaling pathways.

Author Information

Sanjeev Shukla

Rajnee Kanwal

Eswar Shankar

Manish Datt

Mark R. Chance

Pingfu Fu

Gregory T. MacLennan

Sanjay Gupta
Primary Contact  _


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