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Targeting PRPK and TOPK for skin cancer prevention and therapy

Oncogene volume 37, pages 5633–5647 (2018)Cite this article

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Abstract

Solar ultraviolet (sUV) irradiation is a major environmental carcinogen that can cause inflammation and skin cancer. The costs and morbidity associated with skin cancer are increasing, and therefore identifying molecules that can help prevent skin carcinogenesis is important. In this study, we identified the p53-related protein kinase (PRPK) as a novel oncogenic protein that is phosphorylated by the T-LAK cell-originated protein kinase (TOPK). Knockdown of TOPK inhibited PRPK phosphorylation and conferred resistance to solar-simulated light (SSL)-induced skin carcinogenesis in mouse models. In the clinic, acute SSL irradiation significantly increased epidermal thickness as well as total protein and phosphorylation levels of TOPK and PRPK in human skin tissues. We identified two PRPK inhibitors, FDA-approved rocuronium bromide (Zemuron®) or betamethasone 17-valerate (Betaderm®) that could attenuate TOPK-dependent PRPK signaling. Importantly, topical application of either rocuronium bromide or betamethasone decreased SSL-induced epidermal hyperplasia, neovascularization, and cutaneous squamous cell carcinoma (cSCC) development in SKH1 (Crl: SKH1-Hrhr) hairless mice by inhibiting PRPK activation, and also reduced expression of the proliferation and oncogenesis markers, COX-2, cyclin D1, and MMP-9. This study is the first to demonstrate that targeting PRPK could be useful against sUV-induced cSCC development.

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Acknowledgements

This work was supported by The Hormel Foundation and National of Institutes of Health grants CA027502, CA166011, CA187027, and CA196639 (ZD). We thank Dr. Lorenzo A. Pinna (Universita di Padova, Italy) for the pQE-81L-PRPK plasmid, Alyssa Langfald for confocal microscopy analysis, and Dr. Tia Rai and Nicki Brickman for assistance with manuscript submission.

Author contributions

ER and ZD designed the research. ER performed experiments and analyzed results. ER and AMB wrote the manuscript. ER and MHL performed animal studies. TAZ, HGK, KB, FZ, and YYC assisted in performing experiments. JN and YL performed computer modeling. AMB, CC, JE, and SED organized and supplied human patient tissues from University of Arizona Cancer Center.

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    Authors and Affiliations

    1. The Hormel Institute, University of Minnesota, Austin, MN, 55912, USA

      Eunmiri Roh, Mee-Hyun Lee, Tatyana A. Zykova, Feng Zhu, Janos Nadas, Hong-Gyum Kim, Ki Beom Bae, Yan Li, Ann M. Bode & Zigang Dong

    2. China-US Hormel Cancer Institute, 45008, Henan, China

      Mee-Hyun Lee

    3. School of Basic Medicine, Huazhong University of Science and Technology, 430030, Wuhan, China

      Feng Zhu

    4. College of Pharmacy, The Catholic University of Korea, Bucheon, 420-743, Korea

      Yong Yeon Cho

    5. University of Arizona Cancer Center, Tucson, AZ, USA

      Clara Curiel-Lewandrowski, Janine Einspahr & Sally E. Dickinson

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    Roh, E., Lee, MH., Zykova, T.A. et al. Targeting PRPK and TOPK for skin cancer prevention and therapy. Oncogene 37, 5633–5647 (2018). https://doi.org/10.1038/s41388-018-0350-9

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