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Coiled-Coil Domain Containing 80 Suppresses Nonylphenol-Induced Colorectal Cancer Cell Proliferation by Inhibiting the Activation of ERK1/2.

ABSTRACT: Recently, the effect of endocrine-disrupting chemicals on the cancer procession has been a concern. Nonylphenol (NP) is a common environmental estrogen that has been shown to enhance the proliferation of colorectal cancer (CRC) cells in our previous studies; however, the underlying mechanism remains unclear. In this study, we confirmed the increased concentration of NP in the serum of patients with CRC. RNA sequencing was used to explore the differentially expressed genes after NP exposure. We found 16 upregulated genes and 12 downregulated genes in COLO205 cells after NP treatment. Among these differentially expressed genes, we found that coiled-coil domain containing 80 (CCDC80) was downregulated by NP treatment and was associated with CRC progression. Further experiments revealed that the overexpression of CCDC80 significantly suppressed NP-induced cell proliferation and recovered the reduced cell apoptosis. Meanwhile, the overexpression of CCDC80 significantly inhibited the activation of ERK1/2 induced by NP treatment. ERK1/2 inhibitor (PD98059) treatment also suppressed NP-induced CRC cell growth, but the overexpression of CCDC80 did not enhance the effect of ERK1/2 inhibitor. Taken together, NP treatment significantly inhibited the expression of CCDC80, and the overexpression of CCDC80 suppressed NP-induced CRC cell growth by inhibiting the activation of ERK1/2. These results suggest that NP could induce CRC cell growth by influencing the expression of multiple genes. CCDC80 and ERK1/2 inhibitors may be suitable therapeutic targets in NP-related CRC progression.

SUBMITTER: Wang J

PROVIDER: S-EPMC8570822 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Colorectal cancer (CRC) is one of the leading causes of cancer?associated mortality. Asiaticoside (AC) exhibits antitumor effects; however, to the best of our knowledge, the biological function of AC in CRC cells remains unclear. Therefore, the aim of the present study was to investigate the effect of AC on CRC cells. In the present study, CCK?8 and colony formation assays were performed to assess the effects of AV on human CRC cell lines (HCT116, SW480 and LoVo). Mitochondrial membrane potential was examined by JC?1 staining. Cell apoptosis and cell cycle were monitored by flow cytometry, and the expression of genes was evaluated using RT?qPCR and western blot analysis. Furthermore, the biological effect of AC in vivo was detected using a xenograft mouse model. The findings revealed that 2 µM AC suppressed the proliferation of CRC cells in a time? and dose?dependent manner, but had no adverse effects on normal human intestinal FHC cells at a range of concentrations. AC decreased the mitochondrial membrane potential and increased the apoptosis of CRC cells in a dose?dependent manner. Furthermore, AC induced cell cycle arrest at the G0/G1 phase. AC attenuated I?B? phosphorylation in a dose?dependent manner, thereby preventing P65 from entering the nucleus, and resulting in inhibition of the NF??B signaling pathway. In addition, AC significantly reduced the expression of CDK4 and Cyclin D1 in a dose?dependent manner, significantly upregulated the activation of caspase?9 and caspase?3, and decreased the Bcl?2/Bax mRNA ratio. Furthermore, treatment with the NF??B signaling pathway inhibitor JSH?23 significantly increased the cytotoxicity of AC in CRC cells. Findings of the xenograft mice model experiments revealed that AC significantly inhibited colorectal tumor growth in a dose?dependent manner. Overall, AC suppressed activation of the NF??B signaling pathway by downregulating I?B? phosphorylation. This resulted in inhibition of CRC cell viability and an increase of cell apoptosis, which may form the basis of AC use in the treatment of patients with CRC.

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Coiled-Coil Domain Containing 80 Suppresses Nonylphenol-Induced Colorectal Cancer Cell Proliferation by Inhibiting the Activation of ERK1/2.

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