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Title: Inhibitory Effects of Soy Protein Isolate on Intestional Carcinogenesis in Azoxymethane (AOM)-treated Sprague-Dawley Rats are Subsite-specific and Linked to Insulin/IGF Action

Author
item SIMMEN, FRANK
item XIAO, RIJIN
item TILL, RENEE
item HENNINGS, LEAH
item BADGER, THOMAS
item SIMMEN, ROSALIA

Submitted to: American Association of Cancer Research Meeting
Publication Type: Abstract Only
Publication Acceptance Date: 10/15/2006
Publication Date: 11/15/2007
Citation: Simmen, F.A., Xiao, R., Till, R.S., Hennings, L., Badger, T.M., Simmen, R.C. 2007. Inhibitory effects of soy protein isolate on intestional carcinogenesis in azoxymethane (AOM)-treated Sprague-Dawley rats are subsite-specific and linked to insulin/IGF Action [abstract]. In: Proceedings of Fifth American Association of Cancer Research International Conference, "Frontiers in Cancer Prevention Research". p. 117, A. 160.

Interpretive Summary: Soy protein in the diet is thought to be beneficial for certain aspects of human health. In the United States, infants fed soy formula represent the group of Americans who consume the most soy protein. Soy protein isolate (SPI) is the sole protein source in soy formula. Soy foods have been studied for their protective effects against cancers, especially breast cancer. Previous studies from our laboratory have demonstrated that in rat models of colon cancer, SPI reduced the incidence colon cancer. In this work, we have examined how soy counteracts colon cancer by using an animal model that closely resembles human colon cancer. Feeding of soy protein to rats was indeed protective against development of colon cancer. We discovered that this beneficial effect was correlated with reductions in the levels of important hormones such as insulin and leptin that are probably involved in colon cancer development. Our work suggests that SPI may be beneficial for cancer prevention by favorably influencing the hormone production or actions to lower colon cancer risk.

Technical Abstract: Our laboratories have reported inhibitory effects on colon carcinogenesis of soy protein isolate (SPI) in AOM-treated male rats. In the present study, we examined regional and hormonal aspects of the intestinal cancer-preventative actions of SPI. Pregnant Sprague-Dawley dams at gestation day 4 were placed on semi-purified, iso-caloric, AIN-93G diets containing casein (CAS) or SPI (both at 20%, w/w) as the sole protein source. At postnatal day (PND) 3, each litter was culled to 5 males and 5 females (females used in unrelated studies) and rats fed the same diet as their dam. Male progeny were injected subcutaneously with AOM (15mg/kg body weight) at ages PND 50 and PND 57 and killed at 19.5 wks post-AOM. A second group of rats similarly fed CAS or SPI were killed at PND 50 or at 1 or 4 days post-AOM to examine acute responses to carcinogen in proximal vs. distal colon. SPI diet inhibited colon, but not small bowel, tumor incidence at 19.5 wks post-AOM (colon tumor incidence: CAS - 58.6%, SPI - 37.7%, P < 0.05; small bowel tumor incidence: CAS - 17.2%, SPI - 15.1%, P > 0.05). CAS and SPI fed rats did not differ with respect to tumor multiplicity or tumor weight; however, colon tumors of the SPI group had an increased preponderance of gastrointestinal lymphomas. Tumor distribution in colon tended to be more distal than proximal for both diets. Reduction in colon tumor incidence in the SPI group was associated with reduced circulating insulin and leptin and increased circulating IGFBP-1 and IGFBP-3 concentrations; serum IGF-I did not differ. Expression of insulin-responsive SREBP-1c and Fatty Acid Synthase (FAS) genes was suppressed in non-tumor colon tissue of the SPI group. In the second study, AOM treatment induced a transient suppression (day 1) in cell proliferation in crypts of the proximal colon which was maintained in the SPI, but not CAS groups, at day 4. Relative proliferation status of crypt epithelium in distal colon was unaffected by AOM, diet, or time. Apoptosis was transiently induced by AOM (day 1 > PND50 or day 4), with number of TUNEL-positive cells greater for distal than proximal colon. SPI-fed rats manifested reduced numbers of apoptotic cells and phospho-ser15-p53-positive cells in distal colon crypts at day 1, suggesting an SPI-induced resistance to the DNA alkylating effects of AOM. SPI elicited reductions in serum insulin and mRNA abundance of colon SREBP-1c and FAS genes. Results suggest colon-specific inhibitory effects of SPI on AOM-induced carcinogenesis that may involve suppression of insulin/IGF action. Further study of SREBP-1c and FAS in dietary modulation of colon tumorigenesis is warranted.