Abstract A83: Inhibition of hypoxia inducible factor alpha and astrocyte elevated gene-1 mediates cryptotanshionone induced anti-tumor activity in hypoxic PC-3 cells

Abstract

Abstract Although cryptotanshinone (CT) from Salvia miltiorrhiza Bunge was known to exert antitumor activity in liver, breast and prostate cancers, its molecular mechanism under hypoxia still remain unclear. Thus, in the present study, the roles of astrocyte elevated gene 1 (AEG-1) and HIF-1α in crytotanshinone induced antitumor activity were investigated in PC-3 prostate cancer cells under hypoxia. Cryptotanshinone exerted cytotoxicity against prostate cancer cells and suppressed HIF-1α accumulation and transcriptional activity and AEG-1 expression in hypoxic PC-3 cells. Also, AGE-1 was overexpressed in prostate cancer cells and also upregulated along with HIF-1α in hypoxic PC-3 cells. Interestingly, HIF-1α siRNA transfection blocked AEG-1 expression and activated caspase 9/3 and PARP cleavage, while AEG-1 siRNA transfection did not affect HIF-1α activity in hypoxic PC-3 cells. Of note, HIF prolyl hydroxylase inhibitor, dimethyloxalylglycine enhanced the stability of AEG-1 and HIF-1α during hypoxia. In addition, CT also significantly reduced cellular levels of VEGF, a downstream of HIF-1α, and disturbed tube formation in human umbilical vein endothelial cells maintained in conditioned medium of hypoxic PC-3 cells. Consistently, ChIP assay revealed that CT inhibited the binding of HIF-1α to VEGF promoter. Furthermore, CT at 10 mg/kg suppressed the growth of PC-3 cells in BALB/c athymic nude mice by 46.4% compared to untreated control. Consistently, immunohistochemistry revealed decreased expression of Ki-67(proliferation), CD34 (blood vessel), VEGF (angiogenesis), carbonic anhydrase(CA)IX (hypoxic marker) and AEG-1 indices in CT-treated group compared to untreated control. Overall, our findings suggest that CT exerts antitumor activity via inhibition of HIF-1α, AEG1 and VEGF as a potent chemotherapeutic agent. Citation Format: Sung Hoon Kim, Hyojeong Lee, Hanna Hyun Kim, Deok Beom Jung, Eunjung Sohn. Inhibition of hypoxia inducible factor alpha and astrocyte elevated gene-1 mediates cryptotanshionone induced antitumor activity in hypoxic PC-3 cells. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr A83.