Latexin sensitizes leukemogenic cells to gamma-irradiation-induced cell-cycle arrest and cell death through Rps3 pathway.

Abstract

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.

• Authors: Y You, R Wen, R Pathak, A Li, W Li, D St Clair, M Hauer-Jensen, D Zhou, Y Liang
• Journal: Cell death & disease (Cell Death Dis) Vol. 5 Pg. e1493 (Oct 23 2014) ISSN: 2041-4889 [Electronic] England
• PMID: 25341047 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens
• Lxn protein, rat
• Ribosomal Proteins
• ribosomal protein 3

Topics

• Animals
• Antigens (metabolism)
• Carcinogenesis
• Cell Cycle Checkpoints (radiation effects)
• Cell Death (radiation effects)
• Cell Line, Tumor
• Cell Nucleus (metabolism, radiation effects)
• Cell Proliferation (radiation effects)
• Chromosomal Instability (radiation effects)
• DNA Damage
• Gamma Rays
• Gene Knockdown Techniques
• Leukemia (metabolism, pathology)
• Mice
• NIH 3T3 Cells
• Protein Binding (radiation effects)
• Protein Transport (radiation effects)
• Radiation Tolerance (radiation effects)
• Ribosomal Proteins (metabolism)
• Signal Transduction (radiation effects)
• Spindle Apparatus (radiation effects)
• Stress, Physiological (radiation effects)