Chlorophyllin (CHL), a water-soluble salt of chlorophyll, is a blocking agent against 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), and when given post-initiation suppressed IQ-induced rat liver tumors. Paradoxically, at low doses, CHL promoted colon tumorigenesis induced by IQ and 1,2-dimethylhydrazine (DMH) in the rat, but suppressed at higher doses. Recent human trials have raised high hopes for protection by CHL against liver cancer, but there is a need to better define risk versus benefit for CHL against colon cancer, a major cause of US cancer deaths.
Aim 1. PROMOTION IN VIVO - Test for tumor promotion by CHL, chlorophyll, Cu and phytol in the rat; examine expression levels and cellular localization of beta-catenin and E-cadherin in tumors. 1A. Using a dose of CHL that promoted colon tumors in prior studies, test equivalent doses of chlorophyll, copper and phytol in full-length tumor bioassays, with IQ and DMH as initiating agents. 1B. Determine the spectrum and frequency of beta-catenin mutations during colon tumor promotion. 1C. Examine the expression of beta-catenin and downstream targets during colon tumor promotion. 1D. Study E-cadherin expression and sub-cellular localization during colon tumor promotion.
Aim 2. SUPPRESSION IN VIVO - Test for tumor suppression using a CHL dose shown previously to augment apoptosis and cell proliferation in the rat colon, and examine beta-catenin expression. 2A. Demonstrate suppression of DMH- and IQ-induced colon tumors by high dose CHL. 2B. Determine the spectrum and frequency of beta-catenin mutations during colon tumor suppression. 2C. Examine the expression of beta-catenin and downstream targets during colon tumor suppression. 2D. Study beta-catenin/E-cadherin expression and co-localization during colon tumor suppression.
Aim 3. MECHANISMS OF PROMOTION AND SUPPRESSION - Study the effects of CHL on the duality of beta-catenin function: signaling versus cell-cell adhesion 3A. Determine the extent to which CHL alters the expression of beta-catenin transcript. 3B. Examine the phosphorylation, ubiquitination, and proteosomal degradation of beta-catenin. 3C. Determine CHL effects on beta-catenin nuclear export and Adherins junction remodeling. 3D. Assess direct effects of CHL on a downstream target of beta-catenin, c-Jun.
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