Atractylenolide I inhibits colorectal cancer cell proliferation by affecting metabolism and stemness via AKT/mTOR signaling

Background: Atractylenolide I (ATL-1) is a natural herbal compound used in traditional Chinese medicine that has exhibited anti-cancer properties. The anti-tumorigenic activity of ATL-1 against colorectal Cancer (CRC) and the underlying signaling pathways involved in its mechanisms are examined here.

Hypothesis: ATL-1 exerts therapeutic effect against CRC by disrupting glucose metabolism and Cancer stem cell maintenance via Akt/mTOR pathway regulation.

Study design: In vitro studies were performed in COLO205 and HCT116 CRC cell lines and in vivo studies were conducted in a mouse xenograft model of CRC tumor.

Methods: CRC cells were treated with ATL-1 at various concentrations, with or without inhibitors of Akt or mTOR. Cell proliferation, Apoptosis, invasion, stemness maintenance, glucose metabolism, and Akt/mTOR signaling were evaluated. CRC tumor-xenografted mice were treated with an Akt Inhibitor and/or ATL-1, and glucose metabolism and stemness maintenance were examined in tumor tissues.

Results: ATL-1 significantly inhibited the invasion of CRC cells by inducing their Apoptosis, possibly via the excessive production of Reactive Oxygen Species. Glucose metabolism (Warburg effect) was also altered and stem-like traits were suppressed by ATL-1. In addition, ATL-1 effectively acted as an inhibitor or Akt/mTOR by downregulating the phosphorylation of proteins related to the Akt/mTOR pathway. In vivo studies showed that tumor weight and volume were reduced by ATL-1 and that aerobic glycolysis, stemness maintenance, and Akt/mTOR activation were impaired by ATL-1 in colorectal tumors.

Conclusions: ATL-1 acts as an effective agent to suppress colorectal tumor progression, mainly by inhibiting CRC cell proliferation through altering Apoptosis, glucose metabolism, and stem-like behavior. These processes were mediated by the Akt/mTOR signaling pathway both in vitro and in vivo. ATL-1 may be a potential agent to be used in molecular-targeted strategies for Cancer treatment.