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首页> 外文期刊>Journal of cellular biochemistry. >Resistance to 3-HTMC-Induced Apoptosis Through Activation of PI3K/Akt, MEK/ERK, and p38/COX-2/PGE(2) Pathways in Human HT-29 and HCT116 Colorectal Cancer Cells
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Resistance to 3-HTMC-Induced Apoptosis Through Activation of PI3K/Akt, MEK/ERK, and p38/COX-2/PGE(2) Pathways in Human HT-29 and HCT116 Colorectal Cancer Cells

机译：通过激活人类HT-29和HCT116大肠癌细胞中的PI3K / Akt，MEK / ERK和p38 / COX-2 / PGE（2）途径对3-HTMC诱导的细胞凋亡的抗性。

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摘要

Increasing incidence and mortality of colorectal cancer brings the necessity to uncover new possibilities in its prevention and treatment. Chalcones have been identified as interesting compounds having chemopreventive and antitumor properties. In this study, we investigated the effects of the synthetic chalcone derivative 3-hydroxy-3,4,4,5-tetra-methoxy-chalcone (3-HTMC) on proliferation, cell cycle distribution, apoptosis, and its mechanism of action in human colorectal HT-29 (COX-2 sufficient) and HCT116 (COX-2 deficient) cancer cells. We showed that 3-HTMC decreased cell viability in a dose-dependent manner with a more potent antiproliferative effect on HCT116 than HT-29 cells. Flow cytometric analysis revealed G(2)/M cell cycle accumulation in HT-29 cells and significant G(2)/M arrest in HCT116 cells with a subsequent apoptosis shown by appearance of Sub-G1 peak. We demonstrated that 3-HTMC treatment on both cell lines induced apoptotic process associated with overexpression of death receptor DR5, activation of caspase-8 and -3, PARP cleavage, and DNA fragmentation. In addition, 3-HTMC induced activation of PI3K/Akt and MEK/ERK principal survival pathways which delay 3-HTMC-induced apoptosis in both cell lines. Furthermore, COX-2 overexpression in HT-29 cells contributes to apoptosis resistance which explains the difference of sensitivity between HT-29 and HCT116 cells to 3-HTMC treatment. Even if resistance mechanisms to apoptosis reduced chalcone antitumoral potential, our results suggest that 3-HTMC may be considered as an interesting compound for colorectal cancer therapy or chemoprevention. J. Cell. Biochem. 117: 2875-2885, 2016. (c) 2016 Wiley Periodicals, Inc.
机译：大肠癌的发病率和死亡率的增加带来了在其预防和治疗中发现新可能性的必要性。查尔酮已被鉴定为具有化学预防和抗肿瘤特性的有趣化合物。在这项研究中，我们调查了合成查尔酮衍生物3-羟基-3,4,4,5-四甲氧基查尔酮（3-HTMC）对增殖，细胞周期分布，凋亡及其作用机制的影响。人结肠直肠癌HT-29（COX-2不足）和HCT116（COX-2不足）癌细胞。我们显示3-HTMC以剂量依赖的方式降低了细胞活力，对HCT116的抗增殖作用比HT-29细胞强。流式细胞仪分析显示HT-29细胞中的G（2）/ M细胞周期积累和HCT116细胞中显着的G（2）/ M停滞，随后出现的Sub-G1峰表明细胞凋亡。我们证明了在两种细胞系上进行3-HTMC处理均诱导了凋亡过程，该过程与死亡受体DR5的过表达，caspase-8和-3的激活，PARP裂解以及DNA片段化有关。此外，3-HTMC诱导PI3K / Akt和MEK / ERK主要存活途径的激活，从而延迟了3-HTMC诱导的两种细胞系的凋亡。此外，HT-29细胞中COX-2的过表达有助于细胞凋亡，这解释了HT-29和HCT116细胞对3-HTMC处理的敏感性差异。即使对细胞凋亡的抗性机制降低了查耳酮的抗肿瘤潜力，我们的结果也表明3-HTMC可能被认为是用于结直肠癌治疗或化学预防的有趣化合物。 J.细胞。生化。 117：2875-2885，2016。（c）2016 Wiley Periodicals，Inc.

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