期刊
BLOOD
卷 131, 期 26, 页码 2943-2954出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2017-10-813931
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资金
- National Institutes of Health, National Cancer Institute [CA 165469, CA165990]
- Biospecimen Procurement and Translational Pathology [P30 CA177558]
- Office of the Vice President for Research
- Markey Cancer Center
- National Cancer Institute Center [P30 CA177558]
Prostate apoptosis response-4 (Par-4), a proapoptotic tumor suppressor protein, is down-regulated in many cancers including renal cell carcinoma, glioblastoma, endometrial, and breast cancer. Par-4 induces apoptosis selectively in various types of cancer cells but not normal cells. We found that chronic lymphocytic leukemia (CLL) cells fromhuman patients and from E mu-Tcl1 mice constitutively express Par-4 in greater amounts than normal B-1 or B-2 cells. Interestingly, knockdown of Par-4 in human CLL-derived Mec-1 cells results in a robust increase in p21/WAF1 expression and decreased growth due to delayed G1-to-S cell-cycle transition. Lack of Par-4 also increased the expression of p21 and delayed CLL growth in E mu-Tcl1 mice. Par-4 expression in CLL cells required constitutively active B-cell receptor (BCR) signaling, as inhibition of BCR signaling with US Food and Drug Administration (FDA)-approved drugs caused a decrease in Par-4 messenger RNA and protein, and an increase in apoptosis. In particular, activities of Lyn, a Src family kinase, spleen tyrosine kinase, and Bruton tyrosine kinase are required for Par-4 expression in CLL cells, suggesting a novel regulation of Par-4 through BCR signaling. Together, these results suggest that Par-4 may play a novel progrowth rather than proapoptotic role in CLL and could be targeted to enhance the therapeutic effects of BCR-signaling inhibitors.
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