Research Projects
Professor Chris Paraskeva
Apoptosis and novel therapeutic preventive strategies for colorectal cancer (Diet, NSAIDs and Cannabinoids)
Colorectal cancer is the second most common cause of cancer deaths in much of the industrialised world. There is increasing evidence that defects in the regulation of differentiation and apoptosis lead to colorectal cancer. There is now evidence that chemopreventive agents (agents which are believed to reduce the risk of cancer) such as the traditional non-steroidal anti-inflammatory drug (NSAIDs) aspirin, COX-2 selective NSAIDs, butyrate (fermentation product of dietary fibre) and certain vitamins maybe effective through the induction of apoptosis. Recently there has also been a great deal of interest in cannabinoids (plant derived and endogenous) as novel anti-cancer agents and these may, in part, act through the induction of apoptosis. This raises the exciting possibility that research on chemoprevention and apoptosis, which is currently identifying novel targets, could also lead to new adjuvants to existing therapies and/or result in novel treatments for colorectal cancer. The aim of this project (start date October 2005) is to determine the cellular and molecular mechanisms by which chemopreventive agents induce apoptosis with the view of exploiting these agents in the prevention and treatment of bowel cancer. The student will join an active established group working on colorectal cancer in new laboratories which were completely refurbished in 2000.
Modern cell and molecular biology techniques will be used including mammalian cell culture, transfection techniques, confocal microscopy, morphological and biochemical assays for apoptotic cells, biochemical assays for differentiation, western and northern blotting for tumour suppressor gene expression studies, RT-PCR, electromobility gel shift assays.
References
Kaidi, A., Williams, A.C., and Paraskeva, C. (2007) Interaction between beta-catenin and HIF-1 promotes cellular adaptation to hypoxia. Nat. Cell Biol. 9(2), 210-217.
Kaidi, A., Qualtrough, D., Williams, A.C., and Paraskeva, C. (2006) Direct transcriptional upregulation of Cyclooxygenase-2 by Hypoxia-Inducible Factor (HIF)-1 promotes colorectal tumour cell survival and enhances HIF-1 transcriptional activity during hypoxia. Cancer Res. 66, 6683-6691.
Chell, S.D. Witherden, I.R., Dobson, R.R., Moorghen, M., Qualtrough, D., Williams, A.C., and Paraskeva, C. (2006) Increased EP4 receptor expression in colorectal cancer progression promotes cell growth and anchorage independence. Cancer Res. 66, 3106-3113.
Patsos, H.A., Hicks, D.J., Dobson, R., Greenhough, A., Woodman, N., Lane, J.D. Williams, A.C. and Paraskeva, C. (2005) The endogenous cannabinoid, anandamide, induces cell death in colorectal carcinoma cells; a possible role for cyclooxygenase-2. Gut 54, 1741-1750.
Clemo, N.K., Arhel, N.J., Barnes, J.D., Moorghen, M., Packham, G., Paraskeva, C. and Williams, A.C. (2005) The role of the retinoblastoma protein (pRb) in the nuclear localisation of BAG-1: Implications for colorectal tumour cell survival. Biochem. Soc. Transact. 33, 676-678.
Hassan, A.B. and Paraskeva, C. (2005) Colorectal cancer prognosis: is it all mutation, mutation, mutation? Gut 54, 1209-1211.
Patsos, H.A., Hicks, D.J., Greenhough, A., Williams, A.C. and Paraskeva, C. (2005) Cannabinoids and cancer: potential for colorectal cancer therapy. Biochem. Soc. Trans. 33, 712-714.
Chell, S., Patsos, H.A., Qualtrough, D., H-Zadeh, A.M., Hicks, D.J., Kaidi, A., Witherden, I.R., Williams, A.C. and Paraskeva, C. (2005) Prospects in NSAID-derived chemoprevention of Colorectal Cancer. Biochem. Soc. Trans. 33, 667-671.
Barnes, J.D., Arhel, N.J., Lee, S-S., Sharp, A., Al-Okail, M., Packham, G., Hague, A., Paraskeva, C. and Williams, A.C. (2005) Nuclear Bag-1 protects against radiation induced apoptosis in colorectal adenoma derived epithelial cells. Apoptosis 10, 301-311.
Hague, A., Hicks, D.J., Hasan, F., Smartt, H., Cohen, G.M., Paraskeva, C. and MacFarlane, M. (2005) Increased sensitivity to TRAIL-induced apoptosis occurs during the adenoma to carcinoma transition of colorectal carcinogenesis. Brit. J. Cancer 92, 736-742.
Hague, A. and Paraskeva, C. (2004) Apoptosis and disease: a matter of cell fate. Cell Death and Differentiation 11, 1366-1372.
Qualtrough, D., Buda, A., Gaffield, W., Williams, A. and Paraskeva, C. (2004) Hedgehog signalling in colorectal tumour cells: induction of apoptosis with cyclopamine treatment. Int. J. Cancer 110, 831-837.
Smartt, H.J.M., Elder, D.J.E., Hicks, D.J., Williams, N.A. and Paraskeva, C. (2003) Increased NF-κB DNA-binding but not transcriptional activity during apoptosis induced by the COX-2-selective inhibitor NS-398 in colorectal carcinoma cells. Brit. J. Cancer 89, 1358-1365.
Guzm, M. (2003) Cannabinoids: potential anticancer agents. Nature Rev. Cancer 3, 745-755.
Elder, D.J.E., Baker, J.A., Banu, N.A., Moorghen, M. and Paraskeva, C. (2002) Human colorectal adenomas demonstrate a size-dependent increase in epithelial cyclooxygenase-2 expression. J. Pathol. 198, 428-434.
Elder, D.J.E., Halton, D.E., Playle, L.C. and Paraskeva, C. (2002) The MEK/ERK pathway mediates COX-2-selective NSAID-induced apoptosis and induced COX-2 protein expression in colorectal carcinoma cells. Int. J. Cancer 99, 323-327.
Elder, D.J.E. and Paraskeva, C. (1998) Cox-2 inhibitors for colorectal cancer. Nat. Med. 4, 392-393.
Keywords: Colon Cancer, Apoptosis, Chemoprevention
Email:C.Paraskeva@bristol.ac.uk
Please note: This email address is for you to contact Professor Paraskeva if you have any queries regarding the project itself. All other queries and applications should go direct to the Tutor for Graduate Admissions. Please visit the Prospectus page for the full postal or email address for applications.