Cyclovirobuxine D inhibits colorectal cancer tumorigenesis via the CTHRC1‑AKT/ERK‑Snail signaling pathway

Abstract

Cyclovirobuxine D (CVB-D) is an alkaloid, which is mainly derived from Buxus microphylla. It has been reported that CVB-D has positive effects on breast cancer, gastric cancer and other malignant tumors. However, to the best of our knowledge, there are no reports regarding the effects of CVB-D on colorectal cancer (CRC). The purpose of the present study was to determine the anticancer effects of CVB-D and further elucidate its molecular mechanism(s). DLD-1 and LoVo cell lines were selected to evaluate the antitumor effect of CVB-D. Cytotoxicity, viability and proliferation were evaluated by the MTT and colony formation assays. Flow cytometry was used to detect the effects on apoptosis and the cell cycle in CVB-D-treated CRC cells. The migration and invasion abilities of CRC cells were examined by wound healing and Transwell assays. In addition, RNA sequencing, bioinformatics analysis and western blotting were performed to investigate the target of drug action and clarify the molecular mechanisms. A xenograft model was established using nude mice, and ultrasound was employed to assess the preclinical therapeutic effects of CVB-D in vivo. It was identified that CVB-D inhibited the proliferation, migration, stemness, angiogenesis and epithelial-mesenchymal transition of CRC cells, and induced apoptosis and S-phase arrest. In addition, CVB-D significantly inhibited the growth of xenografts. It is notable that CVB-D exerted anticancer effects in CRC cells partly by targeting collagen triple helix repeat containing 1 (CTHRC1), which may be upstream of the AKT and ERK pathways. CVB-D exerted anticancer effects through the CTHRC1-AKT/ERK-Snail signaling pathway. Targeted therapy combining CTHRC1 with CVB-D may offer a promising novel therapeutic approach for CRC treatment.

The Role of CTHRC1 in Regulation of Multiple Signaling and Tumor Progression and Metastasis

“…In addition to the targeted regulation of CTHRC1 by miRNAs, it has been demonstrated that cyclovirobuxine-D could inhibit the progression and metastasis of CRC cells due to the targeting of CTHRC1 [137]. Therefore, CTHRC1 may be a potential target in combination with antitumor drugs in the future, which can promote the research progress of tumor-targeted drugs.…”

Cyclovirobuxine D Induces Apoptosis and Mitochondrial Damage in Glioblastoma Cells Through ROS-Mediated Mitochondrial Translocation of Cofilin

“…In terms of mechanism, several studies have found that CVBD, through the CTHRC1-AKT/ERK-Snail pathway or EGFR-FAK-AKT/ERK1/2-Slug pathway, inhibit cancer tumorigenesis through CVBD inducing mitochondrial apoptosis in cancer cells. Moreover, CVBD causes cancer cell death of autophagy associated with the AKT/mTOR pathway ( 14 – 17 ). Meanwhile, CVBD could active AKT/ERK signaling pathway in T98G and U251.…”

“…Published studies suggest that CVBD has an effect on various cancer cells. For instance, CVBD inhibits colorectal cancer tumorigenesis via the CTHRC1-AKT/ERK-Snail signaling pathway ( 14 ), and exerts anticancer effects by suppressing the EGFR-FAK-AKT/ERK1/2-Slug signaling pathway in human hepatocellular carcinoma ( 15 ). Moreover, CVBD inhibits cell proliferation and induces mitochondria-mediated apoptosis in human gastric cancer cells ( 16 ), and induces autophagy-associated cell death via the Akt/mTOR pathway in MCF-7 human breast cancer cells ( 17 ).…”

Light-Responsive Micelles Loaded With Doxorubicin for Osteosarcoma Suppression

“…Cancer is a disease that seriously affects human health, being one of the primary causes of death all over the worldwide (Tang et al, 2011;Gohlke et al, 2016;Jiang et al, 2020). Osteosarcoma is a highly aggressive tumor originating from the long bones, which is the most frequent primary malignant tumor in children and adolescents, with a wide spectrum of morphology (Hogendoorn et al, 2010;Yen et al, 2018;Sadykova et al, 2020).…”