Astragalus mongholicus Bunge and Curcuma aromatica Salisb. inhibits liver metastasis of colon cancer by regulating EMT via the CXCL8/CXCR2 axis and PI3K/AKT/mTOR signaling pathway

Abstract

Background One of the most challenging aspects of colon cancer (CC) prognosis and treatment is liver-tropic metastasis. Astragalus mongholicus Bunge—Curcuma aromatica Salisb. (AC) is a typical medication combination for the therapy of many malignancies. Our previous studies found that AC intervention inhibits liver metastasis of colon cancer (LMCC). Nevertheless, the comprehensive anti-metastasis mechanisms of AC have not been uncovered. Methods In bioinformatics analysis, RNA-seq data of CC and LMCC patients were collected from TCGA and GEO databases, and differentially expressed genes (DEGs) were identified. The biological processes and signaling pathways involved in DEGs were enriched by GO and KEGG. The protein–protein interaction (PPI) network of DEGs was established and visualized using the Cytocape software, followed by screening Hub genes in the PPI network using Degree value as the criterion. Subsequently, the expression and survival relevance of Hub gene in COAD patients were verified. In the experimental study, the effects of AC on the inhibition of colon cancer growth and liver metastasis were comprehensively evaluated by cellular and animal models. Finally, based on the results of bioinformatics analysis, the possible mechanisms of AC inhibition of colon cancer EMT and liver metastasis were explored by in vivo and in vitro pharmacological experiments. Results In this study, we obtained 2386 DEGs relevant to LMCC from the COAD (colon adenocarcinoma) and GSE38174 datasets. Results of GO gene function and KEGG signaling pathway enrichment analysis suggested that cellular EMT (Epithelial-mesenchymal transition) biological processes, Cytokine-cytokine receptor interaction and PI3K/Akt signaling pathways might be closely related to LMCC mechanism. We then screened for CXCL8, the core hub gene with the highest centrality within the PPI network of DEGs, and discovered that CXCL8 expression was negatively correlated with the prognosis of COAD patients. In vitro and in vivo experimental evidence presented that AC significantly inhibited colon cancer cell proliferation, migration and invasion ability, and suppressed tumor growth and liver metastasis in colon cancer orthotopic transplantation mice models. Concomitantly, AC significantly reduced CXCL8 expression levels in cell supernatants and serum. Moreover, AC reduced the expression and transcription of genes related to the PI3K/AKT pathway while suppressing the EMT process in colon cancer cells and model mice. Conclusions In summary, our research predicted the potential targets and pathways of LMCC, and experimentally demonstrated that AC might inhibit the growth and liver metastasis in colon cancer by regulating EMT via the CXCL8/CXCR2 axis and PI3K/AKT/mTOR signaling pathway, which may facilitate the discovery of mechanisms and new therapeutic strategies for LMCC.

KLF2 inhibits colorectal cancer progression and metastasis by inducing ferroptosis via the PI3K/AKT signaling pathway

“…EMT is characterized by reduced expression of cell adhesion molecule E‐cadherin, with increased expression of N‐cadherin, high expression of vimentin, and transition to mesenchymal cell morphology [ 23 , 24 ]. Interestingly, it has been demonstrated that activation of the PI3K/AKT signaling pathway is a key regulatory mechanism controlling EMT in a variety of cancers [ 34 , 40 ]. An abnormally activated PI3K/AKT pathway can suppress E‐cadherin expression, and upregulate N‐cadherin and vimentin expression, thus promoting tumor cell EMT and metastasis progression [ 41 , 42 ].…”

Natural products targeting macrophages in tumor microenvironment are a source of potential antitumor agents

“…(ARCR) is a typical mixture of medication which can treat a variety of malignancies through impeding M2 polarization of macrophages by regulating the Sp1/ZFAS1/miR-153-3p/CCR5 axis, thereby preventing the development of colon cancer. ARCR at the dose of 6 g/kg/d -1 has no obvious toxicity and adverse reactions in orthotopic transplantation colon cancer model mice (Gu et al, 2022;Liu et al, 2022a). The extract of Cordyceps sinensis accelerates M1 polarization of macrophages by activating the NF-κB signaling pathway (Li et al, 2020).…”

Exploration of the Molecular Mechanism of Curcuma aromatica Salisb’s Anticolorectal Cancer Activity via the Integrative Approach of Network Pharmacology and Experimental Validation

“…Traditional herbal medicine has gained widespread acceptance as an essential alternative and supplementary medicine that benefits cancer patients . Many studies have found that traditional medicinal plants, when taken as adjuvant treatment with radiotherapy, immunotherapy or chemotherapy, can increase quality of life, lengthen survival time, lessen side effects, and boost therapeutic effects. − Owing to its efficiency and lack of negative side effects, the vital medicinal plant Curcuma aromatica Salisb (Cur) has been extensively utilized in traditional medicine. − Several studies have showed the beneficial anticancer benefits of Cur. According to studies, Cur significantly reduces the risk of developing esophageal cancer via halting the reduction of manganese superoxide dismutase in the esophageal epithelium .…”

“… 12 − 14 Owing to its efficiency and lack of negative side effects, the vital medicinal plant Curcuma aromatica Salisb (Cur) has been extensively utilized in traditional medicine. 15 − 17 Several studies have showed the beneficial anticancer benefits of Cur. According to studies, Cur significantly reduces the risk of developing esophageal cancer via halting the reduction of manganese superoxide dismutase in the esophageal epithelium.…”