Leukemia is a leading cause of cancer death. Recently, the latexin (Lxn) gene was identified as a potential tumor suppressor in several types of solid tumors and lymphoma, and Lxn expression was found to be absent or downregulated in leukemic cells. Whether Lxn functions as a tumor suppressor in leukemia and what molecular and cellular mechanisms are involved are unknown. In this study, the myeloid leukemogenic FDC-P1 cell line was used as a model system and Lxn was ectopically expressed in these cells. Using the protein pull-down assay and mass spectrometry, ribosomal protein subunit 3 (Rps3) was identified as a novel Lxn binding protein. Ectopic expression of Lxn inhibited FDC-P1 growth in vitro. More surprisingly, Lxn enhanced gamma irradiationinduced DNA damages and induced cell-cycle arrest and massive necrosis, leading to depletion of FDC-P1 cells. Mechanistically, Lxn inhibited the nuclear translocation of Rps3 upon radiation, resulting in abnormal mitotic spindle formation and chromosome instability. Rps3 knockdown increased the radiation sensitivity of FDC-P1, confirming that the mechanism of action of Lxn is mediated by Rps3 pathway. Moreover, Lxn enhanced the cytotoxicity of chemotherapeutic agent, VP-16, on FDC-P1 cells. Our study suggests that Lxn itself not only suppresses leukemic cell growth but also potentiates the cytotoxic effect of radio- and chemotherapy on cancer cells. Lxn could be a novel molecular target that improves the efficacy of anti-cancer therapy.
|Journal||Cell Death and Disease|
|State||Published - Jan 1 2014|
Bibliographical noteFunding Information:
Acknowledgements. We thank Dr Sabire Ozcan and Megan Sampley for TAP vectors, Carol Beach for mass spectrometry analysis, B Grimes and C Swiderski for technical assistance, and the Markey Cancer Center's Research Communications Office for manuscript editing. This study was supported by the National Center for Advancing Translational Sciences, National Institutes of Health, grant number KL2TR000116 (YL), start-up funding from the Markey Cancer Center at the University of Kentucky (YL), National Cancer Institute, grant number 5P30CA177558-02, National Institutes of Health, and the Edward P Evans Foundation.
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ASJC Scopus subject areas
- Cellular and Molecular Neuroscience
- Cell Biology
- Cancer Research