Abstract 766: Downregulation of MUC4 in pancreatic cancer cells by thymoquinone: A promise for pancreatic cancer therapies

Abstract

Abstract Pancreatic cancer remains one of the most lethal cancers in the world. Currently, the existing therapies have not been optimized and the survival of pancreatic cancer patients remains under 5% after being diagnosed. The high molecular weight glycoprotein Mucin-4 (MUC4) contributes to the regulation of differentiation, proliferation, and metastasis of pancreatic tumor cells. As it is not expressed in normal pancreatic epithelial cells, MUC4 is a promising target for novel cancer therapeutics. Among the natural derived drugs that are being investigated, the extracts from the seeds of the plant Nigella sativa, particularly thymoquinone (TQ), possess multiple benefits, including anti-tumorigenic properties. The main objective of this study was to evaluate the effect of TQ on pancreatic cancer cells and determine the role of the drug on MUC4 expression by analyzing the cytotoxicity, protein and gene expression, and metastatic properties on the MUC4-expressing pancreatic cancer cell line FG/COLO357. Experimental techniques used included western blot, polymerase chain reaction (PCR), transient gene silencing, confocal, and flow cytometry analyses, among other functional assays. The results indicated a decrease in cell viability at increasing concentrations of TQ that correlated with MUC4 downregulation, which occurred thru the proteasomal degradation pathway. The genes that were regulated in FG/COLO357 cells after treatment with TQ were determined by microarray analysis and the results were confirmed by functional assays. It was found that TQ activated the Jun N-terminal Kinase (JNK) and p38 Mitogen-Activated Protein Kinase (MAPK) pathways. As the activation of these pathways is directly related to a decrease in proliferation, survival, and invasion of cancer cells, these results indicate the direct involvement of TQ on the induction of apoptosis of pancreatic cancer cells. The results present evidence that TQ induces the apoptosis of pancreatic cancer cells and the downregulation of MUC4 is related to the apoptotic effect of the drug. In conclusion, TQ, which has a role in downregulation of MUC4 among other anti-tumorigenic properties, represents promise for the development of novel therapies against pancreatic cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 766.