Increased mitotic phosphorylation of histone H3 attributable to AIM-1/Aurora-B overexpression contributes to chromosome number instability.

Phosphorylation of histone H3 at Ser-10 is required for maintenance of properchromosome dynamics during mitosis. AIM-1, a mammalian Ipl1/aurora kinase involved in H3 phosphorylation, is transcriptionally overexpressed in many tumor cell lines. Increased expression of the AIM-1 gene has been observed in human colorectal tumors of advanced grade and stage. Here we report that forced exogenous overexpression of AIM-1 in Chinese hamster embryo cells causes increased mitotic Ser-10 phosphorylation with concomitant induction of lagging chromosomes during mitosis. Lagging chromosomes could also be induced by transfection with mutated histone H3 (S10E), which is thought to maintain Ser-10 in the phosphorylated state. In the present study, chromosome number instability and increased tumor invasiveness were noted in constitutively AIM-1-overexpressing cells in vivo. Increased mitotic Ser-10 phosphorylation was also observed in various colorectal tumor cells with high AIM-1 expression levels. These data suggest that increased H3 histone phosphorylation as a result of AIM-1 overexpression is a major precipitating factor of chromosome instability and, thus, may play a role in carcinogenesis.

Inhibitory effects of estrogenic compounds, 4-nonylphenol and genistein, on 7,12-dimethylbenz[a]anthracene-induced ovarian carcinogenesis in rats.

The modifying effects of dietary feeding of estrogenic compounds, 4-nonylphenol (4-NP) and genistein (GS), on 7,12-dimethylbenz[a]anthracene (DMBA)-induced ovarian carcinogenesis were investigated in female Sprague-Dawley rats. We also assessed the effects of test compounds on proliferating cell nuclear antigen (PCNA) index and the expression of estrogen receptor (ER)-alpha and -beta and androgen receptor (AR) in induced neoplasms. Rats were given a single injection of DMBA (0.01 ml of 0.5- DMBA suspended in olive oil) into their left ovary to induce ovarian neoplasms. They also received the experimental diet containing 25 to 250 ppm 4-NP or GS for 50 weeks, starting one week after the dosing of DMBA. DMBA exposure produced ovarian adenocarcinoma with an incidence of 35% at the end of the study (Week 51). Dietary administration of 4-NP or GS caused significant reduction in the incidence of ovarian adenocarcinoma: 86% reduction (P=0.0218) by feeding of 25 or 250 ppm 4-NP and 25 ppm GS, and 100% reduction (P=0.0042) by feeding of 250 ppm GS. The PCNA index in adenocarcinomas was higher than that of surface ovarian epithelium. ER-alpha, beta and AR were expressed in a variable percentage of moderately and poorly differentiated adenocarcinoma cell nuclei, but not in well-differentiated adenocarcinoma cells. These results might suggest that dietary feeding of estrogenic compounds either synthetic (4-NP) or natural (GS) could act as an inhibitor of DMBA-induced rat ovarian carcinogenesis.

A bitter diterpenoid furanolactone columbin from Calumbae Radix inhibits azoxymethane-induced rat colon carcinogenesis.

The modifying effect of dietary administration of a diterpenoid furanolactone columbin isolated from the crude drug Calumbae Radix (the root of Jateorhiza columba MIERS, Menispermacea) on azoxymethane (AOM)-induced was investigated in male F344 rats. Animals were initiated with AOM (three weekly subcutaneous injections of 15 mg/kg body weight) to induce colonic neoplasms. They were fed the experimental diets mixed with columbin (4, 20, and 100 ppm) for 4 weeks, starting 1 week before the first dosing of AOM and thereafter maintained on the basal diet without columbin. Additional experimental groups included the AOM alone group, the columbin alone group (100 ppm in diet for 4 weeks), and the untreated control group. Dietary feeding of columbin (4, 20, and 100 ppm) during the initiation phase of AOM-induced colon carcinogenesis reduced the incidence and multiplicity of colonic adenocarcinoma and the inhibition by feeding of 20 ppm (incidence: 20%, P=0.0242 and multiplicity: 0.20+/-0.40, P<0.02) and 100 ppm (incidence: 10%, P=0.0029 and multiplicity: 0.10+/-0.30, P<0.002) columbin was significant when compared with the AOM alone group (incidence: 55% and multiplicity: 0.55+/-0.50). Also, columbin administration in diet lowered the number of argyrophilic nucleolar organizer regions protein per nucleus in non-lesional colonic crypts and the blood polyamine content, which are reflected in cell proliferation activity. These results indicate chemopreventive ability of dietary columbin against chemically induced colon tumorigenesis when fed during the initiation phase, providing a scientific basis for chemopreventive ability of columbin against human colon cancer.

Lack of modifying effects of 4-n-octylphenol on 3,2'-dimethyl-4-aminobiphenyl-induced prostate carcinogenesis in rats.

The modifying effects of dietary feeding of an estrogenic compound 4-n-octylphenol on 3,2'-dimethyl-4-aminobiphenyl (DMAB) induced prostatic carcinogenesis were investigated in male F344 rats. The authors also assessed the effects of test compound on proliferating cell nuclear antigen (PCNA) index in induced neoplasms, hyperplastic lesions, and nonlesional glands in the prostrate. Rats were given intraperitoneal injections of DMAB (25 mg/kg body wt) every other week, 10 times, to induce prostatic neoplasms. They also received the experimental diet containing 10 or 100 ppm 4-n-octylphenol for 20 weeks, starting one week after the last dosing of DMAB. DMAB exposure produced prostatic adenocarcinoma with an incidence of 21% at the end of the study (Week 39). Dietary administration of 4-n-octylphenol did not affect the incidence of prostatic adenocarcinoma: 17% in DMAB-->10 ppm 4-n-octylphenol group; and 12% in DMAB-->100 ppm 4-n-octylphenol group. The PCNA indices in adenocarcinomas, hyperplastic lesions, and nonlesional glands in rats treated with DMAB and 4-n-octylphenol were slightly lower than that of the DMAB alone group, but the differences were not statistically significant. These results might suggest that dietary feeding of the weak estrogenic compound 4-n-octylphenol did not have modulating effects on DMAB-induced rat prostatic carcinogenesis.