Abstract
Simple SummaryColon cancer is one of the most common malignant tumors and beberine has been found to exert potential anti-colon cancer activity in vitro and in vivo. In this study, by using proteomics and bioinformatics approaches, we report that berberine may inhibit the proliferation of colon cancer cells by regulating mitochondrial translation and ribosome biogenesis, as well as by promoting calcium mobilization and metabolism of fat-soluble vitamins. Moreover, GTPase ERAL1 and mitochondrial ribosomal proteins MRPL11, 15, 30, 37, 40, and 52 have great potential to serve as potential therapeutic targets for colon cancer treatment.Colon cancer is one of the most lethal malignancies worldwide. Berberine has been found to exert potential anti-colon cancer activity in vitro and in vivo, although the detailed regulatory mechanism is still unclear. This study aims to identify the underlying crucial proteins and regulatory networks associated with berberine treatment of colon cancer by using proteomics as well as publicly available transcriptomics and tissue array data. Proteome profiling of berberine-treated colon cancer cells demonstrated that among 5130 identified proteins, the expression of 865 and 675 proteins were changed in berberine-treated HCT116 and DLD1 cells, respectively. Moreover, 54 differently expressed proteins that overlapped in both cell lines were mainly involved in mitochondrial protein synthesis, calcium mobilization, and metabolism of fat-soluble vitamins. Finally, GTPase ERAL1 and mitochondrial ribosomal proteins including MRPL11, 15, 30, 37, 40, and 52 were identified as hub proteins of berberine-treated colon cancer cells. These proteins have higher transcriptional and translational levels in colon tumor samples than that of colon normal samples, and were significantly down-regulated in berberine-treated colon cancer cells. Genetic dependency analysis showed that silencing the gene expression of seven hub proteins could inhibit the proliferation of colon cancer cells. This study sheds a light for elucidating the berberine-related regulatory signaling pathways in colon cancer, and suggests that ERAL1 and several mitochondrial ribosomal proteins might be promising therapeutic targets for colon cancer.
Highlights
Colon cancer is one of the most common malignant tumors, accompanied with high morbidity and mortality [1]
Seven colon cancer cell lines treated with different concentrations of berberine for 24 or 48 h, and cell viabilities were were treated with different concentrations of berberine for 24 or 48 h, and cell viabilities measured by cell counting kit-8
The results showed that berberine had a broad inon all these different types of colon cancer cell lines in a concentration-dependent manner hibition on all these different types of colon cancer cell lines in a concentration-dependent (Figure 1C), which is consistent with previous reports [27,28,29]
Summary
Colon cancer is one of the most common malignant tumors, accompanied with high morbidity and mortality [1]. The incidence is even higher in the most developed countries [2]. With continuing progress in developing countries, the cases of colorectal cancer worldwide are predicted to increase to 2.5 million in 2035 [3]. Chemotherapy, and radiotherapy are conventional therapies for colon cancer. Each treatment method is associated with specific adverse effects and complications [4]. Biologic agents are broadly used to treat colon cancers [5]. Bevacizumab is a humanized monoclonal antibody against vascular endothelial growth factor A (VEGF-A) and is used for the treatment of metastatic colon cancer [6]. Aflibercept is a recombinant fusion protein consisting of VEGF-binding portion from the extracellular domains of human VEGF receptors
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