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S-phase Arrest (s-phase + arrest)
Selected AbstractsDifferential apoptosis by gallotannin in human colon cancer cells with distinct p53 statusMOLECULAR CARCINOGENESIS, Issue 3 2007Sahar Al-Ayyoubi Abstract Gallotannin (GT), a plant polyphenol, has shown anticarcinogenic activities in several animal models including colon cancer. In our previous study, we showed that GT inhibits 1,2-dimethylhydrazine-induced colonic aberrant crypt foci and tumors in Balb/c mice, thus supporting a role for GT as a chemopreventive agent in colon cancer. However, at the molecular level, GT's mechanism of chemoprevention is still unclear. In this study, we aim at identifying GT's potential molecular mechanisms of action in in vitro studies. We show that GT differentially inhibits the growth of two isogenic HCT-116 (p53+/+, p53,/,) human colon cancer cells versus normal human intestinal epithelial cells (FHs 74Int). DNA flow cytometric analysis showed that GT induced S-phase arrest in both HCT-116 cell lines. Cell-cycle arrest in p53 (+/+) cells was associated with an increase in p53 protein levels and p21 transcript and protein levels. The inhibition of cell-cycle progression of HCT-116 p53 (+/+) cells by GT correlated with a reduction in the protein levels of cyclin D1, pRb, and the Bax/Bcl-2 ratio. Although GT did not induce apoptosis in p53 (+/+) cells, a significant induction of apoptosis was observed in p53 (,/,) cells as shown by TUNEL staining and flow cytometry analysis. Apoptosis induction in p53 (,/,) cells was associated with a significant increase in Bax/Bcl-2 protein levels. Our results demonstrate that GT inhibits the growth of HCT-116 colon cancer cells in a p53-independent manner but exhibits differential sensitivity to apoptosis induction in HCT-116 cells with distinct p53 status. © 2006 Wiley-Liss, Inc. [source] Induction of centrosome amplification and chromosome instability in p53 -deficient lung cancer cells exposed to benzo[a]pyrene diol epoxide (B[a]PDE),THE JOURNAL OF PATHOLOGY, Issue 3 2008K Shinmura Abstract Benzo[a]pyrene diol epoxide (B[a]PDE), the ultimate carcinogenic metabolite of benzo[a] pyrene, has been implicated in the mutagenesis of the p53 gene involved in smoking-associated lung cancer. To further understand the role of B[a]PDE in lung tumour progression, we investigated its effect on the numerical integrity of centrosomes and chromosome stability in lung cancer cells lacking p53. Exposure of p53 -deficient H1299 lung cancer cells to B[a]PDE resulted in S-phase arrest, leading to abnormal centrosome amplification. Analysis of H1299 cells stably expressing fluorescence-tagged centrin (a known centriolar marker) revealed that the centrosome amplification was primarily attributable to excessive centrosome duplication rather than to centriole splitting. Forced expression of POLK DNA polymerase, which has the ability to bypass B[a]PDE,guanine lesions in an error-free manner, suppressed the B[a]PDE-induced centrosome amplification. Fluorescence in situ hybridization analyses with probes specific for chromosomes 2, 3, and 16 revealed that B[a]PDE exposure also led to chromosome instability, which was likely to have resulted from centrosome amplification. We extended these findings to primary lung carcinomas containing non-functional p53, and found a strong association between centrosome amplification and a high level of B[a]PDE,DNA accumulation. Therefore B[a]PDE contributes to neoplasia by inducing centrosome amplification and consequent chromosome destabilization as well as its mutagenic activity. Copyright © 2008 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [source] Olfactomedin 4 promotes S-phase transition in proliferation of pancreatic cancer cellsCANCER SCIENCE, Issue 3 2007Daisuke Kobayashi Induction of olfactomedin 4 (OLFM4GW112/hGC-1) in cancer cells was recently reported to have a novel antiapoptotic action via binding to the potent apoptosis inducer GRIM-19. We sought to clarify undiscovered functions of constitutively expressed OLFM4 in cancer cells. OLFM4 mRNA was highly expressed in pancreatic cancer tissues. In PANC-1 cell cultures, expression was especially elevated during early S phase of the cell cycle. Transduction of small interfering RNA for OLFM4 to decrease mRNA expression caused time-dependent growth inhibition, with typical early S-phase arrest after 6 days. In addition, cell volume increased without increases in multinucleated cells, consistent with premitotic inhibition of DNA synthesis. Inhibition of OLFM4 mRNA expression by small interfering RNA did not promote apoptosis. Taken together, the results indicate that OLFM4 promotes proliferation of PANC-1 cells by favoring transition from the S to G2/M phase. (Cancer Sci 2007; 98: 334,340) [source] Hypoxia-induced irreversible S-phase arrest involves down-regulation of cyclin ACELL PROLIFERATION, Issue 6 2003J. Seim All cells in S phase are immediately arrested upon exposure to extreme hypoxia. During an 18-h extreme hypoxia regime, the cyclin A protein level is down-regulated in cells of both types when in S-phase, and, as we have previously shown, pRB re-binds in the nuclei of all T-47D cells (Åmellem et al. 1996). Hence, pRB is not necessary for the down-regulation of cyclin A during hypoxia. However, our findings indicate that re-oxygenation cannot release pRB from its nuclear binding following this prolonged exposure. The result is permanent S-phase arrest even after re-oxygenation, and this is correlated with a complete and permanent down-regulation of cyclin A in the pRB functional T-47D cells. In contrast, both cell cycle arrest and cyclin A down-regulation in S phase are reversed upon re-oxygenation in non-pRB-functional NHIK 3025 cells after prolonged exposure to extreme hypoxia. Our results indicate that pRB is involved in permanent S-phase arrest and down-regulation of cyclin A after extreme hypoxia. [source] | ||||||||||