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p53-related protein kinase confers poor prognosis and represents a novel therapeutic target in multiple myeloma

Teru Hideshima, Francesca Cottini, Yoshihisa Nozawa, Hyuk-Soo Seo, Hiroto Ohguchi, Mehmet K. Samur, Diana Cirstea, Naoya Mimura, Yoshikazu Iwasawa, Paul G. Richardson, Nikhil C. Munshi, Dharminder Chauhan, Walter Massefski, Teruhiro Utsugi, Sirano Dhe-Paganon and Kenneth C. Anderson

Key Points

  • TP53RK confers poor prognosis in MM patients.

  • TP53RK knockdown or inhibition by IMiDs triggers MM cell apoptosis, validating TP53RK as a novel therapeutic target in MM.

Abstract

p53-related protein kinase (TP53RK, also known as PRPK) is an upstream kinase that phosphorylates (serine residue Ser15) and mediates p53 activity. Here we show that TP53RK confers poor prognosis in multiple myeloma (MM) patients, and, conversely, that TP53RK knockdown inhibits p53 phosphorylation and triggers MM cell apoptosis, associated with downregulation of c-Myc and E2F-1–mediated upregulation of pro-apoptotic Bim. We further demonstrate that TP53RK downregulation also triggers growth inhibition in p53-deficient and p53-mutant MM cell lines and identify novel downstream targets of TP53RK including ribonucleotide reductase-1, telomerase reverse transcriptase, and cyclin-dependent kinase inhibitor 2C. Our previous studies showed that immunomodulatory drugs (IMiDs) downregulate p21 and trigger apoptosis in wild-type-p53 MM.1S cells, Importantly, we demonstrate by pull-down, nuclear magnetic resonance spectroscopy, differential scanning fluorimetry, and isothermal titration calorimetry that IMiDs bind and inhibit TP53RK, with biologic sequelae similar to TP53RK knockdown. Our studies therefore demonstrate that either genetic or pharmacological inhibition of TP53RK triggers MM cell apoptosis via both p53-Myc axis-dependent and axis-independent pathways, validating TP53RK as a novel therapeutic target in patients with poor-prognosis MM.

  • Submitted September 7, 2016.
  • Accepted December 28, 2016.
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