Targeting prpk function blocks colon cancer metastasis

Tatyana Zykova, Feng Zhu, Lei Wang, Haitao Li, Do Young Lim, Ke Yao, Eunmiri Roh, Sang Pil Yoon, Hong Gyum Kim, Ki Beom Bae, Weihong Wen, Seung Ho Shin, Janos Nadas, Yan Li, Weiya Ma, Ann M. Bode, Zigang Dong

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

The biological functions of the p53-related protein kinase (PRPK) remain unclear. We have previously demonstrated that PRPK is phosphorylated by the T-LAK cell-originated protein kinase (TOPK) and that phosphorylated PRPK (p-PRPK) promotes colon cancer metastasis. Here, we analyzed colon adenocarcinomas from 87 patients and found that higher expression levels of p-PRPK were associated with later stages of metastatic dissemination (stage III and IV) as compared with earlier stages (stages I and II). Indeed, levels of p-PRPK were higher in metastatic versus malignant human colon adenocarcinomas. Knocking down PRPK expression attenuated colorectal liver and lung metastasis of colon cancer cells in vivo. An in vitro kinase assay indicated that active PRPK does not phosphorylate p53 directly. We found that PRPK phosphorylates survivin, a regulator of colon cancer metastasis. PRPK phosphorylates survivin at Thr34, which is important for survivin stability. Taken together, our data strongly suggest that the PRPK signaling pathway promotes colon cancer metastasis by modulating survivin stability, and that PRPK could be a new prognostic marker for the survival of colon cancer patients. In addition, we identified an FDA-approved bacteriostatic antibiotic, fusidic acid sodium salt (fusidic acid or FA) as an inhibitor of PRPK, and show that FA combined with 5-fluorouracil (5-FU) inhibited PRPK activity and colon cancer metastasis to the lung in mice. We contend that the combination of FA with 5-FU could be an alternative therapeutic strategy to traditional chemotherapy for colon cancer patients with poor prognosis.

Original languageEnglish (US)
Pages (from-to)1101-1113
Number of pages13
JournalMolecular Cancer Therapeutics
Volume17
Issue number5
DOIs
StatePublished - May 2018

PubMed: MeSH publication types

  • Journal Article
  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

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    Zykova, T., Zhu, F., Wang, L., Li, H., Lim, D. Y., Yao, K., Roh, E., Yoon, S. P., Kim, H. G., Bae, K. B., Wen, W., Shin, S. H., Nadas, J., Li, Y., Ma, W., Bode, A. M., & Dong, Z. (2018). Targeting prpk function blocks colon cancer metastasis. Molecular Cancer Therapeutics, 17(5), 1101-1113. https://doi.org/10.1158/1535-7163.MCT-17-0628