Dr Lesley Stark: Chemoprevention of Colorectal Cancer

Chemoprevention of Colorectal Cancer

Purpose

Compelling evidence from epidemiological, clinical, animal and laboratory studies indicates that aspirin and related non-steroidal anti-inflammatory drugs (NSAIDs) have anti-tumour activity against colorectal cancer and the potential for primary prevention of this disease. However, the detrimental side effects of NSAIDs limit their use. The purpose of our research is to understand the fundamental mechanisms by which NSAIDs act against colorectal cancer in order to identify targets for the development of safer alternatives.

Approach

Pathways that are modulated by aspirin/NSAIDs are being identified in cell line models of colorectal cancer. Clinical studies and animal models are being used to examine the in vivo relevance of these results. Studies are focussed on the NF-kappaB signalling pathway and in particular, subnuclear localisation as a method for regulating the NF-kappaB pathway and apoptosis.

Progress

Identified activation of the NF-kappaB signal transduction pathway as a key mechanism for the pro-apoptotic activity of aspirin and related NSAIDs (Fig. 1).
Made the novel observation that the RelA component of NF-kappaB translocates to the nucleolus in response to NSAIDs and other stress inducing agents.
Demonstrated that nucleolar targeting of RelA is causally involved in the apoptotic response to these agents.
Demonstrated that aspirin activates the NF-kappaB pathway through p38-mediated phosphorylation/degradtion of cyclinD1/inhibition of CDK4 (Fig. 1).
Shown that aspirin activates the NF-kappaB pathway and mediates apoptosis in intestinal neoplasia in vivo using the APC Min and HT29 xenograft models of human colorectal cancer.

Key Publications

Stark, L.A. and Taliansky, M. Old and new faces of the nucleolus. Workshop on the Nucleolus and Disease.
EMBO Rep 10(1):35-40, 2009
PubMed Abstract
Stark, L.A.; Reid, K.; Sansom, O.J.; Din, F.V.; Guichard, S.; Mayer, I.; Jodrell, D.I.; Clarke, A.R. and Dunlop, M.G. Aspirin activates the NF-{kappa}B signalling pathway and induces apoptosis in intestinal neoplasia in two in vivo models of human colorectal cancer.
Carcinogenesis 28(5):968-976, 2007 PubMed Abstract
Thoms, H.C.; Dunlop, M.G. and Stark, L.A. p38-mediated inactivation of cyclin D1/cyclin-dependent kinase 4 stimulates nucleolar translocation of RelA and apoptosis in colorectal cancer cells.
Cancer Res 67(4):1660-1669, 2007
PubMed Abstract
Stark, L.A. and Dunlop, M.G. Nucleolar sequestration of RelA (p65) regulates NF-kappaB-driven transcription and apoptosis. Mol Cell Biol 25(14):5985-6004, 2005 PubMed Abstract
Stark, L.A.; Din, F.V.; Zwacka, R.M. and Dunlop, M.G. Aspirin-induced activation of the NF-kB signaling pathway: a novel mechanism for aspirin-mediated apoptosis in colon cancer cells.
FASEB J 15(7): 1273-1275, 2001
PubMed Abstract

Lab Members

Current lab members involved in this work are:

Dr Lesley Stark – Principle investigator
Dr Hazel Thoms – Postdoctoral scientist
Richard Brady – Clinical Fellow
Jim Simpson - Research assistant

Cell Signalling, The Nucleolus and Chemoprevention of Colorectal Cancer (Edinburgh Cancer Research Centre)
Professor Malcolm Dunlop: Colon Cancer Genetics Group and Academic Coloproctology

Model for the pro-apoptotic effects of NSAIDs and the regulation of NF-kappaB-driven transcription and apoptosis by nucleolar targeting of RelA (Stark and Dunlop 2005).

Aspirin induces nucleolar translocation
of RelA

Future Work and Ongoing Projects

Identify the mechanisms involved in defining the sub-nuclear localisation of RelA
Identify the mechanism by which nucleolar translocation of RelA mediates apoptosis
Identify the pathways targeted by aspirin upstream of p38
Use animal models to determine the role of nucleolar translocation of RelA in normal cell function.