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Midostaurin inhibits hormone-refractory prostate cancer PC-3 cells by modulating nPKCs and AP-1 transcription factors and their target genes involved in cell cycle

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Frontiers in Biology

Abstract

Background

The development of prostate cancer from a clinically localized, hormone-naive state to a hormonerefractory phenotype involves a complex interplay of protein kinase C (PKC) and activator protein-1 (AP-1). Therefore, the present study aimed to uncover the roles of PKC and AP-1 through midostaurin-mediated regulation—a multi-target protein kinase inhibitor.

Methods

Androgen Receptor-negative, hormone-refractory prostate cancer cells (PC-3) were used as an in-vitro model system. The effect of midostaurin on cell viability was assessed by an MTT assay. Expression studies on PKC-α, PKC-d, different AP-1 transcription factors, and AP-1 regulating genes were analyzed by semiquantitative RT-PCR, and protein levels of Bcl-2 were evaluated by western blotting.

Results

Midostaurin decreased the viability of hormone-refractory PC-3 cells. Furthermore, midostaurin significantly induced the transcripts of apoptotic-mediated PKC-d, tumor suppressor p53, cell cycle inhibitor p21cip1/waf1, death receptor TNF-α, pro-apoptotic Bax, and Caspase-8, and eventually inhibited the expression of pro-survival PKC-ε, pro-oncogene c-Jun, c-Fos, Fra-1, positive growth regulator cyclin D1, and anti-apoptotic Bcl-2. In addition, midostaurin also decreased the protein expression of anti-apoptotic Bcl-2.

Conclusion

The present study provided evidence that midostaurin suppresses tumor growth and induces apoptosis in hormone-refractory PC-3 cells via modulation of PKC-d and PKC-ε expression, and regulation of PMA-altered c-Jun, c-Fos, and Fra-1 AP-1 transcription factors and their target genes involved in cell cycle regulation (cyclin D1, p53, p21, Bcl-2, and TNF-α). Thus, pharmacological targeting of PKC and AP-1 factors may have therapeutic potential against hormone-refractory prostate cancer.

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Acknowledgements

The authors wish to express their gratitude to the Department of Science and Technology-Promotion of University Research and Scientific Excellence [DST-PURSE; SR/59/Z- 23/2010/38(c)] and the University Grant Commission-Centre with Potential for Excellence in Particular Area [UGC-CPEPA; 8-2/2008(NS/PE)], New Delhi for providing financial support. The authors also wish to express their gratitude to the Department of Microbiology and Biotechnology, Bangalore University, Bengaluru for providing DST-FIST, UGC-SAP, and department facilities.

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Authors and Affiliations

  1. Department of Microbiology and Biotechnology, Bangalore University, Jnana Bharathi, Bengaluru, 560 056, Karnataka, India

    Kavya Krishnappa, Naveen Kumar Mallesh, Srikantaradhya Chidananda Sharma & Doddamane Manjulakumari

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  1. Kavya Krishnappa
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  2. Naveen Kumar Mallesh
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  3. Srikantaradhya Chidananda Sharma
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  4. Doddamane Manjulakumari
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Correspondence to Kavya Krishnappa or Doddamane Manjulakumari.

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Krishnappa, K., Mallesh, N.K., Sharma, S.C. et al. Midostaurin inhibits hormone-refractory prostate cancer PC-3 cells by modulating nPKCs and AP-1 transcription factors and their target genes involved in cell cycle. Front. Biol. 12, 421–429 (2017). https://doi.org/10.1007/s11515-017-1475-x

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