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首页> 外文期刊>Molecular Carcinogenesis >Checkpoint kinase 1-mediated phosphorylation of Cdc25C and bad proteins are involved in antitumor effects of loratadine-induced G2/M phase cell-cycle arrest and apoptosis.
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Checkpoint kinase 1-mediated phosphorylation of Cdc25C and bad proteins are involved in antitumor effects of loratadine-induced G2/M phase cell-cycle arrest and apoptosis.

机译：Checkpoint激酶1介导的Cdc25C和不良蛋白的磷酸化与氯雷他定诱导的G2 / M期细胞周期阻滞和凋亡有关。

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In this study, we first demonstrated that loratadine (LOR), a promising world widely used oral anti-histamine, effectively inhibits growth of tumors derived from human colon cancer cells (COLO 205) in an in vivo setting. In vitro study demonstrated that the anti-tumor effects of LOR in COLO 205 cells were mediated by causing G(2)/M phase cell growth cycle arrest and caspase 9-mediated apoptosis. Cell-cycle arrest induced by LOR (75 microM, 24 h) was associated with a significant decrease in protein levels of cyclin B1, cell division cycle (Cdc) 25B, and Cdc25C, leading to accumulation of Tyr-15-phosphorylated Cdc2 (inactive form). Interestingly, LOR (75 microM, for 4 h) treatment also resulted in a rapid and sustained phosphorylation of Cdc25C at Ser-216, leading to its translocation from the nucleus to the cytoplasm because of increased binding with 14-3-3. We further demonstrated that the LOR-induced Cdc25C (Ser-216) phosphorylation was blocked in the presence of checkpoint kinase 1 (Chk1) specific inhibitor (SB-218078). The cells treated with LOR in the presence of Chk1 specific inhibitor (SB-218078) were then released from G(2)/M arrest into apoptosis. These results implied that Chk1-mediated phosphorylation of Cdc25C plays a major role in response to LOR-mediated G(2)/M arrest. Although the Chk1-mediated cell growth arrest in response to DNA damage is well documented, our results presented in this study was the first report to describe the Chk1-mediated G(2)/M cell-cycle arrest by the histamine H1 antagonist, LOR.
机译：在这项研究中，我们首先证明了氯雷他定（LOR）是一种有前途的世界广泛使用的口服抗组胺药，可在体内有效抑制人结肠癌细胞（COLO 205）衍生的肿瘤的生长。体外研究表明，LOR在COLO 205细胞中的抗肿瘤作用是通过引起G（2）/ M期细胞生长周期停滞和caspase 9介导的凋亡而介导的。 LOR（75 microM，24 h）诱导的细胞周期停滞与细胞周期蛋白B1，细胞分裂周期（Cdc）25B和Cdc25C的蛋白质水平显着降低有关，从而导致Tyr-15磷酸化的Cdc2积聚（不活跃形成）。有趣的是，LOR（75 microM，持续4小时）处理还导致Cdc25C在Ser-216处快速而持续地磷酸化，由于与14-3-3的结合增加，导致Cdc25C从细胞核转移到细胞质。我们进一步证明，在存在检查点激酶1（Chk1）特异性抑制剂（SB-218078）的情况下，LOR诱导的Cdc25C（Ser-216）磷酸化被阻断。然后在存在Chk1特异性抑制剂（SB-218078）的情况下用LOR处理的细胞从G（2）/ M阻滞释放进入凋亡。这些结果表明，Cdc25C的Chk1介导的磷酸化在响应LOR介导的G（2）/ M逮捕中起主要作用。尽管Chk1介导的细胞生长停滞对DNA损伤的反应已得到充分记录，但我们在这项研究中提出的结果是描述由组胺H1拮抗剂LOR介导的Chk1介导的G（2）/ M细胞周期停滞的第一份报告。 。

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