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Cardamonin represses proliferation, invasion, and causes apoptosis through the modulation of signal transducer and activator of transcription 3 pathway in prostate cancer

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Abstract

The pleiotropic transcription factor, signal transducer and activator of transcription 3 (STAT3) is often aberrantly activated in a wide variety of cancers and plays a pivotal role in tumor initiation, promotion and progression. Targeting deregulated STAT3 activation by small molecule inhibitors is generally considered as an important therapeutic strategy. Hence, in the present study, we evaluated the potential of cardamonin (CD), a 2′,4′-dihydroxy-6′-methoxychalcone, to modulate STAT3 activation in prostate cancer (PC) cells and found that this chalcone can indeed exhibit significant anticancer effects through negatively regulating STAT3 activation by diverse molecular mechanism(s). CD suppressed STAT3 phosphorylation, nuclear translocation and DNA binding ability in PC cells. Computational modeling revealed that CD can bind directly to the Src Homology 2 domain of STAT3 and also effectively inhibit its dimerization. CD was also found to significantly reduce the migratory/invasive potential of PC cells through the downregulation of various oncogenic proteins. Overall, the data indicates that the potential application of CD as a STAT3 blocker can mitigate both the growth and survival of PC cells.

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Abbreviations

STAT3:

Signal transducer and activator of transcription 3

CD:

Cardamonin

PC:

Prostate cancer

PSA:

Prostate-specific antigen

SH2:

Src Homology 2

MTT:

3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT)

EMSA:

Electrophoretic mobility shift assay

PFA:

Paraformaldehyde

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Acknowledgments

Kwang Seok Ahn and Jae-Young Um were supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIP) (NRF-2015R1A4A1042399). This work was also supported by NUHS Basic seed Grant (T1-BSRG 2015-02) and Ministry of Education Tier I to G. Sethi. G. Sethi was also supported by the John Nott Cancer Fellowship from Cancer Council, Western Australia. The authors would also like to extend their sincere appreciation to the Deanship of Scientific Research at King Saud University for its funding of this research through the Research Group Number (RG-1435-081). Alan Prem Kumar is supported by grants from the National Medical Research Council of Singapore (R-713-000-177-511), NUHS Bench-to-Bedside-To-Product (R-184-000-243-515), the National Research Foundation Singapore and the Singapore Ministry of Education under its Research Centres of Excellence initiative to Cancer Science Institute of Singapore, National University of Singapore and by the NCIS Yong Siew Yoon Research Grant through donations from the Yong Loo Lin Trust. The work was also supported by Department of Science and Technology (No. SR/FT/LS-142/2012) to Salundi Basappa.

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    Authors and Affiliations

    1. Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore

      Jingwen Zhang, Sakshi Sikka, Kodappully S. Siveen, Alan Prem Kumar & Gautam Sethi

    2. Cancer Science Institute of Singapore, Centre for Translational Medicine, 14 Medical Drive, #11-01M, Singapore, 117599, Singapore

      Sakshi Sikka & Alan Prem Kumar

    3. Department of Korean Pathology, College of Korean Medicine, Kyung Hee University, #47, Kyungheedae-gil, 1 Hoegi-Dong Dongdaemun-Gu, Seoul, 130-701, Republic of Korea

      Jong Hyun Lee, Jae-Young Um & Kwang Seok Ahn

    4. School of Biomedical Sciences, Faculty of Health Sciences, Curtin University, Perth, WA, 6009, Australia

      Alan Prem Kumar & Gautam Sethi

    5. Department of Biological Sciences, University of North Texas, Denton, TX, 76203, USA

      Alan Prem Kumar

    6. Department of Botany and Microbiology, College of Science, King Saud University, Riyadh, 11451, Saudi Arabia

      Arunachalam Chinnathambi & Sulaiman Ali Alharbi

    7. Laboratory of Chemical Biology, Department of Chemistry, Bangalore University, Central College Campus, Palace Road, Bangalore, 560001, India

      Basappa

    8. Department of Studies in Chemistry, Manasagangotri, University of Mysore, Mysore, 570006, India

      Kanchugarakoppal S. Rangappa

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    1. Jingwen Zhang
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    Correspondence to Kwang Seok Ahn.

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    Jingwen Zhang and Sakshi Sikka have contributed equally to this work.

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    Zhang, J., Sikka, S., Siveen, K.S. et al. Cardamonin represses proliferation, invasion, and causes apoptosis through the modulation of signal transducer and activator of transcription 3 pathway in prostate cancer. Apoptosis 22, 158–168 (2017). https://doi.org/10.1007/s10495-016-1313-7

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