Abstract 1819: Over-expression of PIM1 kinase contributes to CYP24A1 gene up-regulation in prostate cancer.

Abstract The traditional role of vitamin D is in the control of calcium homeostasis and bone mineralization. Over the past 2 decades, studies have demonstrated that vitamin D is useful for the prevention and treatment of various cancers. 24-hydroxylase, encoded by CYP24A1 gene, is the key enzyme which inactivates vitamin D. Increased expression of CYP24A1 has been found in several human tumors. CYP24A1 is regulated directly by 1,25(OH)2D3 (1,25D3) through genomic signaling. Studies have revealed that protein kinase signaling pathways may also be involved in the regulation of CYP24A1 expression. By screening a chemical compound library, we discovered that small chemical compounds with inhibitory activity toward protein kinases including PIM1 and HIPK2 inhibited CYP24A1 expression. Furthermore, siRNA-mediated PIM1 knockdown reduced 1,25D3-induced CYP24A1 mRNA and protein expression in human prostate cancer PC3 cells. In contrast, HIPK2 knockdown had no effect. The serine/threonine kinase PIM1 has been implicated as an oncogene in various human cancers including lymphomas, gastric, colorectal and prostate carcinomas. We analyzed mRNA expression of CYP24A1 and PIM1 in 26 case-matched pairs of human benign and malignant prostate by qRT-PCR. CYP24A1 expression was increased in 6 out of 26 malignant prostate samples compared to benign lesions (> 1.5 fold). PIM1 expression was increased in 10 out of 26 malignant prostate samples compared to benign lesions (> 1.5 fold). Five of the 6 samples with increased CYP24A1 in malignant lesions also had increased PIM1 expression. Fisher's exact test shows that increased CYP24A1 expression is significantly associated with increased PIM1 expression in malignant prostate (P = 0.0184). These data indicate that PIM1 may be involved in increased CYP24A1 expression in prostate cancer. This study was supported by NIH/NCI grants 5R01CA067267 and 5R01CA095045. Citation Format: Wei Luo, Mikhail Chernov, Yingyu Ma, Candace Johnson, Donald Trump. Over-expression of PIM1 kinase contributes to CYP24A1 gene up-regulation in prostate cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1819. doi:10.1158/1538-7445.AM2013-1819