Abstract
Colorectal cancer is the leading cause of cancer related deaths in the United States. Although it is preventable, thousands of lives are lost each year in the U.S. to colorectal cancer than to breast cancer and AIDS combined. In colon cancer, the formation and progression of precancerous lesions like aberrant crypt foci and polyps is associated with the up-regulation of cycloxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS) and hydroxy methyl glutaryl CoA reductase (HMG-CoA reductase). The current review will focus on the signaling pathway involving COX-2 and HMG-CoA reductase enzymes and their downstream effectors in signaling mechanism. Cancer cells need huge pools of both cholesterol and isoprenoids to sustain their unlimited growth potential. Cholesterol by modulating caveolae formation regulates several signaling molecules like AKT, IGFR, EGFR and Rho which are involved in cell growth and survival. Cholesterol is also essential for lipid body formation which serves as storage sites for COX-2, eicosanoids and caveolin-1. Experimental studies have identified important mechanisms showing that COX-2, caveolin-1, lipid bodies and prenylated proteins is involved in carcinogenesis. Therefore multi-target, multi-drug approach is the ideal choice for effective colon cancer chemoprevention. This review will give an overview of the two pathways, their signaling networks, and the interactions between the components of the two networks in the activation and regulation of cell signaling involving growth/survival and explain the rationale for colon cancer chemoprevention using COX-2 inhibitors and statins.
Highlights
The systems biology approach to gene regulation involves the study of networks of genes between well-characterized pathways
Understanding the differences between the cross-talk that occurs in normal cells, and the cross-talk that occurs in cancer cells will provide insight that could lead to new strategies for treating cancer
While the effect of statins on caveolae disruption and caveolin-1 function may be related to its ability to block cholesterol formation, the effect of statins on proteins like lamin B, Ras and Rho is due to the unavailability of cholesterol biosynthetic pathway intermediates called isorenoids
Summary
The systems biology approach to gene regulation involves the study of networks of genes between well-characterized pathways. The fundamental challenge is to predict how a certain drug interacts with the cellular and molecular components of the signaling network. This will help in understanding the expected behavior of a drug interaction with the signaling network. The identification of the signaling network or crosstalk among various signal pathways is of fundamental importance in developing novel strategies for prevention and treatment of cancer. Comparative analysis of these networks is central to our understanding of the biological systems. Understanding the differences between the cross-talk that occurs in normal cells, and the cross-talk that occurs in cancer cells will provide insight that could lead to new strategies for treating cancer
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