Chiu SJ, Chao JI, Lee YJ, Hsu TS.. 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: 63-70

Department of Life Science, Tzu Chi University, Hualien 970, Taiwan.
Toxicology Letters (Impact Factor: 3.26). 07/2008; 179(2):63-70. DOI: 10.1016/j.toxlet.2008.04.004
Source: PubMed


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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Available from: Jui-I Chao, Aug 27, 2014
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    ABSTRACT: Securin overexpression correlates with poor prognosis in various tumours. We have previously shown that securin depletion promotes radiation-induced senescence and enhances radiosensitivity in human cancer cells. However, the underlying molecular mechanisms and the paracrine effects remain unknown. In this study, we showed that radiation induced senescence in securin-deficient human breast cancer cells involving the ATM/Chk2 and p38 pathways. Conditioned medium (CM) from senescent cells promoted the invasion and migration of non-irradiated cancer and endothelial cells. Cytokine assay analysis showed the up-regulation of various senescence-associated secretory phenotypes (SASPs). The IL-6/STAT3 signalling loop and platelet-derived growth factor-BB (PDGF-BB)/PDGF receptor (PDGFR) pathway were important for CM-induced cell migration and invasion. Furthermore, CM promoted angiogenesis in the chicken chorioallantoic membrane though the induction of IL-6/STAT3- and PDGF-BB/PDGFR-dependent endothelial cell invasion. Taken together, our results provide the molecular mechanisms for radiation-induced senescence in securin-deficient human breast cancer cells and for the SASP responses.
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    • "Treatment of colon cancer cells with oxaliplatin leads to activation of p38 MAP kinase, which subsequently phosphorylates gamma-H2AX and securin. These phosphorylation events contribute to the cell apoptosis induced by the compound [19,20]. "
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    • "In contrast, securin has been identified as an oncogene and a marker of invasiveness due to its overexpression in a variety of tumors [23], and has been found to regulate tumor cell proliferation and tumorigenesis [24], [25]. In our previous studies, anticancer agents such as oxaliplatin and fisetin were shown to induce cancer cell death through down-regulation of securin expression [26]–[28]. BPR0L075 possesses anti-tumor and anti-angiogeneic activities by inhibiting the function of microtubules, especially at the metaphase to anaphase transition in mitosis [6], [7]. Securin is also a protein that is involved in control of the metaphase-anaphase transition and anaphase onset. "
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