Prostate apoptosis response-4 (Par-4), a proapoptotic tumor suppressor protein, is downregulated 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 from human patients and from Eµ-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 Eμ-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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This work was supported by the National Institutes of Health, National Cancer Institute (CA 165469) (N.M., V.M.R., and S.B.). M.K.M. and J.R.R. were supported by National Institutes of Health, National Cancer Institute T32 grant CA165990. This research was supported by the Biospecimen Procurement and Translational Pathology shared resource facilities of the University of Kentucky Markey Cancer Center (P30 CA177558). The Flow Cytometry & Cell Sorting core facility is supported in part by the Office of the Vice President for Research, the Markey Cancer Center, and a National Cancer Institute Center Core Support Grant (P30 CA177558) to the University of Kentucky Markey Cancer Center.
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McKenna, Mary Kathryn; Noothi, Sunil K.; Alhakeem, Sara S.; Oben, Karine Z.; Greene, Joseph T.; Mani, Rajeswaran; Perry, Kathryn L.; Collard, James P.; Rivas, Jacqueline R.; Hildebrandt, Gerhard C.; Fleischman, Roger A.; Durbin, Eric B.; Byrd, John C.; Wang, Chi; Muthusamy, Natarajan; Rangnekar, Vivek M.; and Bondada, Subbarao, "Novel Role of Prostate Apoptosis Response-4 Tumor Suppressor in B-Cell Chronic Lymphocytic Leukemia" (2018). Microbiology, Immunology, and Molecular Genetics Faculty Publications. 133.
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