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

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.

• Authors: Elise C Ambrose, Jacki Kornbluth
• Journal: Apoptosis : an international journal on programmed cell death (Apoptosis) Vol. 14 Issue 10 Pg. 1227-36 (Oct 2009) ISSN: 1573-675X [Electronic] Netherlands
• PMID: 19653100 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• RNA, Messenger
• RNA, Small Interfering
• Green Fluorescent Proteins
• Etoposide
• UCKL1 protein, human
• Uridine Kinase
• Caspase 3
• Caspase 7
• Staurosporine

Topics

• Apoptosis (drug effects)
• Caspase 3 (metabolism)
• Caspase 7 (metabolism)
• Cell Cycle (drug effects)
• Cell Proliferation (drug effects)
• Cytotoxicity, Immunologic (drug effects)
• Down-Regulation (drug effects)
• Etoposide (pharmacology)
• Gene Expression Regulation, Neoplastic (drug effects)
• Gene Silencing (drug effects)
• Green Fluorescent Proteins (metabolism)
• Humans
• K562 Cells
• Killer Cells, Natural (cytology, drug effects, immunology)
• Neoplasms (enzymology, immunology, pathology)
• RNA, Messenger (genetics, metabolism)
• RNA, Small Interfering (metabolism)
• Staurosporine (pharmacology)
• Time Factors
• Uridine Kinase (genetics, metabolism)