Abstract 5196: CDF inhibits cell migration by inactivating cancer stem cell markers, and expression of VEGF, IL-6 and miR-21 in human pancreatic and prostate cancer cells under hypoxic condition

Abstract

Abstract Hypoxia has been well recognized to cause therapeutic resistance associated with solid tumors and considered to play critical roles in other of biological events including cell growth and proliferation, cell survival, angiogenesis, immunosurveillance, tumor invasion and metastasis. Hypoxia-inducible factor (HIF) 1α, a master transcription factor that regulates hypoxia responsive genes, plays critical roles in the adaptation of tumor cells to a hypoxic microenvironment. Tumor hypoxia and over-expression of HIF-1α have been reportedly associated with resistance to radiation therapy and chemotherapy, increased risk of invasion and metastasis and poor clinical prognosis, all of which leads to higher mortality of patients diagnosed with solid tumors. Emerging evidence suggest that hypoxia and HIF signaling pathways leads to the acquisition of epithelial-to-mesenchymal transition (EMT), maintenance of cancer stem cell (CSC) functions, and causing inflammatory tumor microenvironment, which contributes to therapeutic resistance; however, the exact mechanisms by which hypoxia/HIF regulates these events are not fully understood. Here, we demonstrates that hypoxia increases the productions of VEGF and IL-6, and increased expression of CSC marker genes such as Nanog, Oct4, EZH2 as well as miR-21, an oncogenic miRNA, in human pancreatic cancer (AsPC-1 and MiaPaCa-2) and prostate cancer (PC-3 and LNCaP) cells. The treatment of these cells with CDF, a novel curcumin analog that was previously shown to be biologically superior than curcumin as an anti-tumor agent both in vitro and in vivo, inhibited the productions of VEGF, IL-6, Nanog, Oct4 and EZH2 mRNAs, as well as down regulated the expression of miR-21 in these cells under hypoxic condition. CDF also decreased cell migration in pancreatic and prostate cancer cells under hypoxic condition as documented by wound healing assay. Taken together, these data suggest for the first time that the anti-tumor effect of CDF could in part be due to inhibition of tumor hypoxic pathways including the inhibition of CSC markers and thereby reconditioning the tumor microenvironment, which would be useful for overcoming therapeutic resistance. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5196. doi:1538-7445.AM2012-5196