Abstract #1738: Curcumin decreases Sp protein expression and pancreatic cancer cell and tumor growth

Abstract

Recent studies have shown that Specificity protein 1 (Sp1) is overexpressed in pancreatic tumors and is associated with poor prognosis for these patients. In addition to Sp1, Sp3 and Sp4 are also overexpressed in many tumors and together Sp1, Sp3 and Sp4 regulate many genes that play an important role in tumor growth, angiogenesis, survival and metastasis. Since Sp proteins are overexpressed in tumor tissue when compared to the normal tissues, this suggests that Sp transcription factors are excellent targets for cancer chemotherapy. Recent studies showed that phytochemical curcumin (diferuloylmethane), a spice component, inhibited tumor growth and proliferation in various cancer cell lines and is reported to act through inhibition of NFkB. In this study we show that curcumin inhibited proliferation of Panc-28 and L3.6pL pancreatic cancer cell lines and growth inhibitory IC₅₀ values were 12.4 and 9.7 µM for Panc-28 and L3.6pL cells respectively. Curcumin also induced apoptosis and decreased expression of cyclin D1, survivin, vascular endothelial growth factor (VEGF) and its receptor VEGFR1 & VEGFR2 and epidermal growth factor receptor (EGFR). Curcumin also decreased constitutive levels of NFkB and this was associated with down regulation of p65. Sp knockdown by RNA interference also decreased p65 expression demonstrating that in pancreatic cancer cells p65 is an Sp dependent gene. Treatment with 10 - 50 µM curcumin decreased Sp1, Sp3 and Sp4 protein expression in both Panc-28 and L3.6pL cells and curcumin induced Sp downregulation was not inhibited by the proteosome inhibitor MG132. We also observed that at a dose of 100 mg/kg/day given intraperitoneally, curcumin decreased pancreatic tumor weight and growth in athymic nude mice bearing L3.6pL cells as xenografts. In addition, we also observed decrease in Sp-dependent genes such as VEGF, survivin, cyclin D1 in both in vivo and in vitro studies. The mechanism responsible for curcumin-dependent Sp proteins degradation is currently under investigation.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 1738.