407 Current Trends in Biotechnology and Pharmacy Vol. 6 (4) 407-417 October 2012, ISSN 0973-8916 (Print), 2230-7303 (Online) Abstract Curcumin is a natural yellow phenolic compound extracted from the Indian spice, turmeric ( Curcuma longa). Several studies demonstrated the ability of curcumin to inhibit events associated with the promotion of cancer. We investigated the effects curcumin on human colon cancer cells in vitro and further examined the molecular mechanisms of curcumin induced cell death. The signaling adapter p62/SQSTM1, a multifunctional protein implicated in autophagy, apoptosis, cell signaling pathways and tumorigenesis, is one of the potential targets for anti-cancer therapy. In this study, we demonstrate a dose and time-dependent down-regulation of p62/SQSTM1 expression by curcumin that correlates with increase in the loss of viability of human colon cancer cells. We also found that curcumin enhanced phospho-ERK expression and ceramide (Cer) generation in human colon cancer cells. However, the present study also shows that, curcumin-induced p62/SQSTM1 degradation, up-regulation of ERK phosphorylation, Cer generation and cell death can be reversed by extracellular anti-oxidants such as glutathione (GSH) and N-acetyl cysteine (NAC). Overall, our results suggest that down regulation of p62/SQSTM1 and up-regulation of phospho-ERK and Cer generation may contribute to the anti-proliferative effects of curcumin against human colon cancer cells. Keywords: p62/SQSTM1, phospho-ERK, Curcumin, Ceramide, Apoptosis, GSH Introduction Curcumin, a well-known chemo-preventive agent, has been shown to possess anti- inflammatory and anti-oxidant activities (1). It also has been reported as a potent inhibitor of mutagenesis and carcinogenesis (2). The anti- cancer property of curcumin has been extensively investigated in various cancer cells and in different laboratory animal models of cancer. Curcumin was found to inhibit cellular proliferation, and enhance apoptosis in a variety of human cancer cell lines in vitro (3). Currently, curcumin is in clinical trials for the treatment of cancers of pancreas, colon and multiple myeloma (3). The proposed mechanism of anti-tumor action of curcumin in majority of these studies involves suppression of NF-kB related gene products expression (4). Previously, we have shown that curcumin induces generation of reactive oxygen species (ROS) which leads to caspase dependent and independent apoptosis (5). We have also reported the modulation of curcumin-induced apoptosis by using PI3K inhibitor in breast carcinoma cell lines (6). The signaling adapter p62/SQSTM1 is a multifunctional protein implicated in autophagy, apoptosis, cell signaling pathways and Curcumin Induces Human Colon Cancer Cell death via p62/SQSTM1 Degradation, Phospho-ERK Up-regulation and Ceramide Generation Mahendra Patel, Faisal Thayyullathil, Shahanas Chathoth, Abdulkader Hago, Siraj Pallichankandy, Anees Rahman and Sehamuddin Galadari* Cell Signaling Laboratory, Department of Biochemistry, Faculty of Medicine and Health Sciences, UAE University, PO Box 17666, Al Ain, UAE. *For Correspondence – sehamuddin@uaeu.ac.ae Role of p62/SQSTM1 in curcumin-induced cell death