Ursolic acid inhibits the metastasis of colon cancer by downregulating ARL4C expression

Oncol Rep. 2024 Feb;51(2):27. doi: 10.3892/or.2023.8686. Epub 2023 Dec 22.

Abstract

Ursolic acid (UA), a natural pentacyclic triterpenoid, is known to exhibit various biological activities and anticancer effects. However, the underlying anticancer mechanism is not fully understood to date. The present study aimed to investigate the antimetastatic effect of UA through ADP‑ribosylation factor like GTPase 4C (ARL4C) in colon cancer. A lung metastasis model of colon cancer in nude mice was established through tail vein injection. A Cell Counting Kit‑8 assay was used to investigate the proliferation of colon cancer cells. Transwell assays were used to detect cell migration and invasion. The expression levels of proteins including ARL4C, matrix metallopeptidase 2 (MMP2), phosphorylated (p)‑AKT and p‑mTOR were measured using western blot analysis. Immunohistochemistry was used to determine the protein expression level in tissues. ARL4C ubiquitination levels were analysed using immunoprecipitation and western blotting. The results indicated that UA inhibits the metastasis of colon cancer in vivo and in vitro. The expression of ARL4C in human colon cancer tissue was significantly higher than that in adjacent tissues and its high expression level was associated with lymph node metastases and tumour stage. UA treatment significantly decreased ARL4C and MMP2 protein levels and inhibited the AKT/mTOR signalling pathway. Overexpression of ARL4C reversed the inhibitory effect of UA on the invasion and migration of HCT‑116 and SW480 cells, as well as the expression and secretion of MMP2 protein. In addition, UA and an AKT signalling pathway inhibitor (LY294002) induced the ubiquitination of the ARL4C protein, which was reversed by a proteasome inhibitor (MG‑132). Collectively, it was revealed in the present study that UA served as a novel solution to relieve colon cancer metastasis by inducing the ubiquitination‑mediated degradation of ARL4C by modulating the AKT signalling pathway. Thus, UA may be a promising treatment option to prolong the survival of patients with colon cancer metastasis.

Keywords: ADP ribosylation factor like GTPase 4C; AKT; colon cancer; metastasis; ursolic acid.

MeSH terms

  • ADP-Ribosylation Factors
  • Animals
  • Cell Proliferation
  • Colonic Neoplasms* / drug therapy
  • Humans
  • Matrix Metalloproteinase 2 / metabolism
  • Mice
  • Mice, Nude
  • Proto-Oncogene Proteins c-akt / metabolism
  • TOR Serine-Threonine Kinases / metabolism
  • Triterpenes* / pharmacology
  • Triterpenes* / therapeutic use
  • Ursolic Acid

Substances

  • Ursolic Acid
  • Proto-Oncogene Proteins c-akt
  • Matrix Metalloproteinase 2
  • TOR Serine-Threonine Kinases
  • Triterpenes
  • ARL4C protein, human
  • ADP-Ribosylation Factors

Grants and funding

The present study was supported from the Scientific Research Fund of Shanghai Sixth People's Hospital Medical Group (grant no. 22-LY-02), the One Hundred Talents Project of Putuo Hospital, Shanghai University of Traditional Chinese Medicine (grant no. 2022-RCQH-03), the Science and Technology Innovation Project of Putuo District Health System (grant no. ptkwws202307) and the National Natural Science Foundation of China (grant no. 82305141).