Regulation of gamma-H2AX and securin contribute to apoptosis by oxaliplatin via a p38 mitogen-activated protein kinase-dependent pathway in human colorectal cancer cells.
ABSTRACT Oxaliplatin, a chemotherapeutic drug, induces DNA strand breaks leading to apoptosis in colorectal cancer cells. gamma-H2AX is a phosphorylated histone H2AX that can act as a marker of DNA double-strand breaks (DSBs). It has been shown that securin proteins were over-expressed in a variety of cancer cells. However, the roles of gamma-H2AX and securin on the oxaliplatin-induced apoptosis in human colorectal cancer cells remain unclear. Treatment of oxaliplatin (1-10 microM for 6-24h) persistently induced gamma-H2AX formation and inhibited securin protein expression via a time- and concentration-dependent manner in HCT116 securin-wild type colorectal cancer cells. Compared with HCT116 securin-wild type cells, the induction of apoptosis and persistent gamma-H2AX formation by oxaliplatin was reduced in the HCT116 securin-null colorectal cancer cells. Furthermore, the blockage of caspases by specific caspase inhibitors reduced the levels of gamma-H2AX proteins and cytotoxicity but increased securin protein expression in the oxaliplatin-exposed cells. The gene knockdown of H2AX by transfection with a short interfering RNA of H2AX enhanced the oxaliplatin-induced cell death. Interestingly, the phosphorylation of p38 mitogen-activated protein kinase (MAPK) was markedly increased by oxaliplatin. Pre-treatment of a specific p38 MAPK inhibitor SB202190 reduced gamma-H2AX proteins and increased securin protein expression in the oxaliplatin-treated cells. Our findings suggest that p38 MAPK may oppositely regulate securin protein expression and gamma-H2AX formation in the oxaliplatin-induced apoptosis of human colorectal cancer cells.
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ABSTRACT: Bioactive compounds are considered safe and have been shown to alter genetic and epigenetic profiles of tumor cells. However, many of these changes have been reported at molecular concentrations higher than physiologically achievable levels. We investigated the role of the combinatorial effects of epigallocatechin gallate (EGCG), a predominant polyphenol in green tea, and sodium butyrate (NaB), a dietary microbial fermentation product of fiber, in the regulation of survivin, which is an overexpressed anti-apoptotic protein in colon cancer cells. For the first time, our study showed that the combination treatment induced apoptosis and cell cycle arrest in RKO, HCT-116 and HT-29 colorectal cancer cells. This was found to be regulated by the decrease in HDAC1, DNMT1, survivin and HDAC activity in all three cell lines. A G2/M arrest was observed for RKO and HCT-116 cells, and G1 arrest for HT-29 colorectal cancer cells for combinatorial treatment. Further experimentation of the molecular mechanisms in RKO colorectal cancer cells revealed a p53-dependent induction of p21 and an increase in nuclear factor kappa B (NF-κB)-p65. An increase in double strand breaks as determined by gamma-H2A histone family member X (γ-H2AX) protein levels and induction of histone H3 hyperacetylation was also observed with combination treatment. Further, we observed a decrease in global CpG methylation. Taken together, these findings suggest that at low and physiologically achievable concentrations, combinatorial EGCG and NaB are effective in promoting apoptosis, inducing cell cycle arrest and DNA-damage in colorectal cancer cells.Experimental Cell Research 05/2014; · 3.37 Impact Factor
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ABSTRACT: Compared with low linear energy transfer (LET) radiation, carbon–ion radiation has been proved to induce high frequency of more complex DNA damages, including DNA double strands (DSBs) and non-DSB clustered DNA lesions. Chemotherapeutic drug doxorubicin has been reported to elicit additional H2AX phosphorylation in polyploidy. Here, we investigated whether mitotic DNA damage induced by high-LET carbon–ion radiation could play the same role. We demonstrate that impairment of post-mitotic G1 and S arrest and abrogation of post-mitotic G2-M checkpoint failed to prevent mis-replication of damaged DNA and mis-separation of chromosomes. Meanwhile, mitotic slippage only nocodazole-related, cytokinesis failure and cell fusion collectively contributed to the formation of binucleated cells. Chk1 and Cdh1 activation was inhibited when polyploidy emerged in force, both of which are critical components for mitotic exit and cytokinesis. Carbon–ion radiation irrelevant of nocodazole incurred additional DNA breaks in polyploidy, manifesting as structural and numerical karyotype changes. The proliferation of cells given pre-synchronization and radiation was completely inhibited and cells were intensely apoptotic. Since increased chromosomal damage resulted in extensive H2AX phosphorylation during polyploidy, we propose that the additional γ-H2AX during polyploidy incurred by carbon–ion radiation provides a final opportunity for these dangerous and chromosomally unstable cells to be eliminated.Toxicology Letters 10/2014; 230(1):36–47. · 3.36 Impact Factor
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ABSTRACT: Phosphorylated p38 (p-p38) played a pivotal role in the regulation of disease progression and correlated with tumor prognosis. Here, we characterized the prognostic effect of p-p38 in colorectal cancer (CRC). Three hundred and sixteen CRC patients in stages I-III were recruited in this study. P-p38 expression was semi-quantitatively evaluated using tissue microarrays and immunohistochemistry staining. Overall survival (OS), disease-free survival (DFS), local failure-free survival (LFFS), and distant metastasis-free survival (DMFS) of patient subgroups, segregated by p-p38 expression level and clinical stage, were compared using Kaplan-Meier analysis. We found that p-p38 was overexpressed in 48.1 % (152/316) CRC tissues, whereas low or deficiently expressed in normal adjacent epithelia. Overexpression of p-p38 predicted poor OS (P < 0.001), DFS (P = 0.002), LFFS (P = 0.016), and DMFS (P = 0.025) in CRC. Importantly, patient subgroups in the early stage (stages I + II) and with low p-p38 had similar OS, PFS, LFFS, and DMFS probabilities to that of stage I, whereas those with high p-p38 were similar to stage III disease. In addition, for stage III disease, the subgroup with low p-p38 had a similar survival probability to that of stage I, whereas the subgroup with high p-p38 had the worst survival. Multivariate Cox analysis confirmed that p-p38 was indeed a significantly independent factor for death, recurrence, and distant metastases in CRC. Our results demonstrated that p-p38 was a negative independent prognostic factor for CRC. Complementing TNM staging with p-p38 might refine the risk definition more accurately for a subset of patients.Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine. 07/2014;
Toxicology Letters 181 (2008) 140
Contents lists available at ScienceDirect
journal homepage: www.elsevier.com/locate/toxlet
Corrigendum to “Regulation of gamma-H2AX and securin contribute
to apoptosis by oxaliplatin via a p38 mitogen-activated protein
kinase-dependent pathway in human colorectal cancer cells”
[Toxicol. Lett. 179 (June(2)) (2008) 63–70]
S.-J. Chiu∗, J.-I. Chao, Y.-J. Lee, T.-S. Hsu
Tzu Chi University, College of Life Sciences, Department of Life Science, 701, Section 3, Chung-Yang Road, Hualien 970, Taiwan
The authors regret that they have incorrectly cited a recent publication in Cancer Treatment Reviews entitled “Oxaliplatin for the
treatment of cisplatin-resistant cancer: a systematic review”, Stordal, B., Pavlakis, N., Davey, R., 2007. Cancer Treatment Reviews 33(4),
347–357, and have significantly misrepresented the Stordal et al. findings.
To correct the error will require the removal of one sentence from the introduction and one sentence from the Discussion.
In the Introduction, on the first page, the fourth line, the following sentence should be removed “Oxaliplatin has been widely accepted
as potentially useful for the treatment of cisplatin-resistant cancer (Stordal et al., 2007).”
In the Discussion, on the fifth page, 2nd paragraph, third line, the following sentence should be removed “Oxaliplatin has been reported
to be useful for the treatment of cisplatin-resistant cancer (Stordal et al., 2007).”
The authors of the cited article have also provided a Letter to the Editor that explains their view.
DOIs of original articles:10.1016/j.toxlet.2008.04.004, 10.1016/j.toxlet.2008.07.003
∗Corresponding author. Tel.: +886 3 8565301; fax: +886 3 8572526.
E-mail address: firstname.lastname@example.org (S.-J. Chiu).
0378-4274/$ – see front matter © 2008 Elsevier Ireland Ltd. All rights reserved.