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Inhibition of Apoptosis in Colon Tumors Induced in the Rat by 2-Amino-3-methylimidazo[4,5-f]quinoline¹

Department of Environmental Biochemistry, University of Hawaii, Honolulu, Hawaii 96822 [R. H., R. D.], and Department of Pathology, St. Francis Medical Center, Honolulu, Hawaii 96817 [D. H., H. L.]

The cooked meat mutagen 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) produces tumors at multiple sites in the F344 rat, including adenocarcinomas of the colon. In the present study, the development of IQ-induced colorectal tumors was shown to be accompanied by the progressive inhibition of programmed cell death. This was associated with increased expression of the antiapoptosis protein Bcl-2 and decreased expression of bax, a known activator of apoptosis. Carcinomas bearing high levels of bcl-2 expression exhibited low levels of p53, the tumor suppressor protein that in some circumstances has been shown to down-regulate bcl-2. Because they lack mutations in the genes commonly associated with increased cell proliferation (APC, Ki-ras, and p53) and show no evidence of microsatellite instability, IQ-induced colon tumors might arise via the deregulation of bcl-2 expression, leading to inhibition of programmed cell death.

¹ Supported by grants from the NIH (CA 65525) and U.S. Department of Agriculture (HAW 00626H and T-STAR Grant 95-34135-1775). Support for R. H. was provided by a grant from the Howard Hughes Medical Institute through the Undergraduate Biological Sciences Education Program.

² To whom requests for reprints should be addressed, at Department of Environmental Biochemistry, University of Hawaii at Manoa, Henke Hall 329, 1800 East-West Road, Honolulu, HI 96822. Phone: (808) 956-2010; Fax: (808) 956-5037; E-mail: dashwood@hawaii.edu.

Received 6/20/96. Accepted 8/15/96.

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