Targeting AKT with costunolide suppresses the growth of colorectal cancer cells and induces apoptosis in vitro and in vivo

Abstract

Background Colorectal cancer (CRC) is a clinically challenging malignant tumor worldwide. As a natural product and sesquiterpene lactone, Costunolide (CTD) has been reported to possess anticancer activities. However, the regulation mechanism and precise target of this substance remain undiscovered in CRC. In this study, we found that CTD inhibited CRC cell proliferation in vitro and in vivo by targeting AKT. Methods Effects of CTD on colon cancer cell growth in vitro were evaluated in cell proliferation assays, migration and invasion, propidium iodide, and annexin V-staining analyses. Targets of CTD were identified utilizing phosphoprotein-specific antibody array; Costunolide-sepharose conjugated bead pull-down analysis and knockdown techniques. We investigated the underlying mechanisms of CTD by ubiquitination, immunofluorescence staining, and western blot assays. Cell-derived tumour xenografts (CDX) in nude mice and immunohistochemistry were used to assess anti-tumour effects of CTD in vivo. Results CTD suppressed the proliferation, anchorage-independent colony growth and epithelial-mesenchymal transformation (EMT) of CRC cells including HCT-15, HCT-116 and DLD1. Besides, the CTD also triggered cell apoptosis and cell cycle arrest at the G2/M phase. The CTD activates and induces p53 stability by inhibiting MDM2 ubiquitination via the suppression of AKT’s phosphorylation in vitro. The CTD suppresses cell growth in a p53-independent fashion manner; p53 activation may contribute to the anticancer activity of CTD via target AKT. Finally, the CTD decreased the volume of CDX tumors without of the body weight loss and reduced the expression of AKT-MDM2-p53 signaling pathway in xenograft tumors. Conclusions Our project has uncovered the mechanism underlying the biological activity of CTD in colon cancer and confirmed the AKT is a directly target of CTD. All of which These results revealed that CTD might be a new AKT inhibitor in colon cancer treatment, and CTD is worthy of further exploration in preclinical and clinical trials.

Costunolide Induces Apoptosis via the Reactive Oxygen Species and Protein Kinase B Pathway in Oral Cancer Cells

“…Moreover, CTD represses hepatic fibrosis through the WW domain-containing protein-2-mediated Notch3 degradation and enhances the sensitivity of doxorubicin treatment to chronic myeloid leukemia cells through the PI3K/AKT pathway [ 40 , 41 ]. Our previous study also confirmed that CTD inhibited cell growth and triggered apoptosis through the MDM2/P53 pathway by targeting AKT in colon cancer [ 42 ]. Obviously, CTD is a potential inhibitor in cancer therapy.…”

Back to the Roots—An Overview of the Chemical Composition and Bioactivity of Selected Root-Essential Oils

“…Apart from that, recent results revealed that COS inhibited colorectal cancer cell proliferation and triggered apoptosis in vitro and in vivo by targeting the AKT-MDM2-p53 signaling pathway. Consequently, this compound was found to be worthy for further exploration in preclinical and clinical trials [ 287 ]. Moreover, COS has emerged as a potential tumor-specific candidate in skin cancer treatment.…”

Umbelliferone and scopoletin target tyrosine kinases on fibroblast-like synoviocytes to block NF-κB signaling to combat rheumatoid arthritis

“…24-well Transwell chambers (8 μm pore size; Corning, NY, United States) were used as published ( Huang H et al, 2021 ). For single-cell migration assessment, HFLS-RA cells (4 × 10 4 /well) in 200 μl serum-free medium were seeded in the upper chambers and treated with 20 µM celecoxib, umbelliferone, and scopoletin, respectively.…”