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 irradiation-induced 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.
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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.
You, Y.; Wen, R.; Pathak, R.; Li, A.; Li, W.; St. Clair, D.; Hauer-Jensen, M.; Zhou, D.; and Liang, Ying, "Latexin Sensitizes Leukemogenic Cells to Gamma-Irradiation-Induced Cell-Cycle Arrest and Cell Death through Rps3 Pathway" (2014). Toxicology and Cancer Biology Faculty Publications. 37.