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Downregulation of uridine-cytidine kinase like-1 decreases proliferation and enhances tumor susceptibility to lysis by apoptotic agents and natural killer cells

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Abstract

Natural killer (NK) cells target and kill tumor cells by direct anti-tumor cytotoxicity. NK lytic-associated molecule (NKLAM) is a protein involved in this cytolytic function. Acting as an E3 ubiquitin ligase, NKLAM binds to and ubiquitinates a novel protein, uridine-cytidine kinase like-1 (UCKL-1), targeting it for degradation. However, UCKL-1’s function in tumor cell survival and NK cell cytotoxicity is unknown. UCKL-1’s homology to uridine kinases and over expression in tumor cells suggests a role for UCKL-1 in tumor growth and/or survival. We propose that NKLAM and UCKL-1 interact in the tumor cell, where degradation of UCKL-1 leads to increased tumor cell apoptosis. Here we use RNA interference to downregulate UCKL-1 expression in K562 erythroleukemia cells. It was seen that downregulation of UCKL-1 initiated apoptosis and slowed the cell cycle, resulting in lower growth in the small interfering UCKL-1 RNA treated K562 cell culture. In addition, the chemotherapeutic agent staurosporine was seen to be more effective in inducing cell death by apoptosis in UCKL-1 depleted K562 cells compared with controls. We also found that UCKL-1 depleted K562 cells were more susceptible to NK mediated cytolysis than controls. These results indicate a role for UCKL-1 in tumor cell survival and suggest possible therapeutic potential of UCKL-1 inhibitors in cancer treatment.

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Acknowledgments

This material is based on work supported by a merit review grant from the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, and Biomedical Laboratory Research and Development.

Conflict of interest statement

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Pathology, Saint Louis University School of Medicine, Doisy Research Center, Room 343, 1100 South Grand Blvd., St. Louis, MO, 63104, USA

    Elise C. Ambrose

  2. Department of Pathology, Saint Louis University School of Medicine, Doisy Research Center, Room 323, 1100 South Grand Blvd., St. Louis, MO, 63104, USA

    Jacki Kornbluth

  3. Department of Veterans Affairs Medical Center, St. Louis, MO, 63106, USA

    Jacki Kornbluth

Authors
  1. Elise C. Ambrose
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  2. Jacki Kornbluth
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Correspondence to Jacki Kornbluth.

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Ambrose, E.C., Kornbluth, J. Downregulation of uridine-cytidine kinase like-1 decreases proliferation and enhances tumor susceptibility to lysis by apoptotic agents and natural killer cells. Apoptosis 14, 1227–1236 (2009). https://doi.org/10.1007/s10495-009-0385-z

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