Abstract #2962: Apigenin downregulates XIAP protein expression through HDAC1 in prostate cancer

X-linked Inhibitor of Apoptosis protein (XIAP), a member of the inhibitor of apoptosis family of proteins (IAP), is one of the major IAPs over-expressed in prostate cancer that might be a promising molecular target for effective treatment of this disease. Emerging evidence suggests that flavonoids present in fruits and vegetables play important roles in inhibiting carcinogenesis. The plant flavone apigenin has shown promising anticancer effects, but its potential in overcoming apoptosis resistance in prostate cancer cells needs further investigation. Nuclear and cytoplasmic shuttling of XIAP is important in the process of apoptosis. Studies have shown that under normal physiological conditions, XIAP-remains in the cytoplasm, whereas XIAP nuclear translocation has been linked to cellular hypoxia, a condition commonly observed in malignant cells. XAF1 (XIAP-associated factor-1) is a nuclear protein that directly interacts with endogenous XIAP, causing its sequestration in the nucleus. A histone-modifying enzyme, histone deacetylase (HDAC), and histone acetyltransferases, including cyclic-AMP response element binding protein (CBP) and p300, physically interact with XIAP protein controlling gene transcriptional activation and repression. Exposure of androgen-refractory human prostate cancer PC-3 cells, possessing high constitutive XIAP expression, to apigenin (5-40\#956;M) resulted in decreased HDAC1 enzyme activity and reduction in its protein expression. Transfection of HDAC1 siRNA into PC-3 cells resulted in significant reductions in XIAP and survivin protein expression levels, similar to those observed with apigenin and embelin (XIAP inhibitor) exposure. Furthermore, exposure of cells to apigenin reduced the nuclear presence of CBP and XIAP proteins, and diminished XIAP nuclear interaction with CBP. Apigenin inhibited c-IAP1, c-IAP2 and survivin in a dose-dependent manner, which correlated with increased expression of Bax and Bad protein in these cells. Significant increases in caspase-3, caspase-9 and p21/Waf1 expression and PARP cleavage were observed after apigenin exposure. In vivo studies of PC-3 xenografts in athymic nude mice further demonstrated that feeding apigenin orally at doses of 20- and 50-\#956;g/mouse/day over an 8 week period resulted in decreased protein expressions of XIAP and survivin along with inhibition of tumor growth. Our findings suggest that apigenin has the potential to overcome IAP activity in prostate cancer cells, thereby promoting apoptosis. Its activity in this process makes it an attractive candidate for further development as a chemopreventive/ therapeutic agent in the management of prostate cancer and its precursors.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 2962.