Astragalus Mongholicus Bunge-Curcuma Aromatica-Paridis Rhizoma Inhibits Metastasis of Colon Cancer via the PERK/eIF2α/ATF4 Signaling Pathway

  OBJECTIVE  To investigate the mechanism of anti-colorectal cancer growth and metastasis-related effects of Astragalus mongholicus Bunge-Curcuma aromatica-Paridis Rhizoma (Qi-Zhu-Zao) pairing through PERK/eIF2α/ATF4 signaling pathway mediating endoplasmic reticulum stress.

  METHODS  Twenty-four BALB/c male mice were randomly divided into sham-operated group, model group, 5-FU (5-fluorouracil) group (25 mg·kg^-1), and Qi-Zhu-Zao high dose group (5.85 g·kg^-1), Qi-Zhu-Zao low dose group(2.925 g·kg^-1) (n=6) to construct a mouse model of colorectal cancer in situ transplantation tumor, and the intervention effect of Qi-Zhu-Zao combination on tumor growth was assessed by the change of tumor volume size after 15 days of administration; the intervention effect of Qi-Zhu-Zao combination on tumor growth was assessed by H&E. Pathological staining was used to evaluate the effect of Qi-Zhu-Zao combination on the liver and tumor tissues of mice. The changes of MDA, SOD and GSH-Px levels were detected by enzyme-linked immunosorbent assay (ELISA); the expression of PERK/eIF2α/ATF4 signaling pathway and EMT-related proteins were detected by protein immunoblotting (Western blot).

  RESULTS  Compared with the model group, the tumor volume was significantly reduced (P < 0.000 1), liver and spleen metastases were less pronounced in the Qi-Zhu-Zao high-dose group, and histopathological staining results of liver tissue and tumor produced changes in oxidative stress indicators SOD, MDA, and GSH-Px, upregulation of ER stress-related proteins p-PERK, p-IF2α, and ATF4, etc., upregulated the protein expression levels of E-Cadherin, downregulated N-Cadherin, Vimentin, and Snail, and inhibited the EMT process (P < 0.01 or P < 0.05).

  CONCLUSION  In this paper, we investigated the regulatory mechanism related to the inhibition of colorectal cancer growth and metastasis by the combination of Qi-Zhu-Zao trigonal medicine, and demonstrated that it may inhibit the growth and metastasis of colorectal cancer by activating the PERK/eIF2α/ATF4 pathway to induce sustained ER stress and affect the EMT process of colorectal cancer.