Tanshinone IIA induces ferroptosis in colorectal cancer cells through the suppression of SLC7A11 expression via the PI3K/AKT/mTOR pathway.

BACKGROUND: Colorectal cancer (CRC) is a malignant tumor of the digestive system with high incidence rate and mortality. Tanshinone IIA (Tan IIA) plays an anti-cancer role in a variety of cancer cells. Here, we aimed to elucidate the therapeutic effects and potential mechanism of Tan IIA in CRC. METHODS: OUMS23 cells were treated with 0, 5, 10, or 20 μM Tan IIA, and CRC mice were exposed to 20 μM Tan IIA + SLC7A11 plasmid. Edu and flow cytometry analyses were performed to assay cell proliferation and apoptosis, respectively. An Iron Assay Kit was used for determining total iron and Fe(2+) levels in intracellular and tumor tissues. Lipid reactive oxygen species (ROS) production was evaluated by flow cytometry. SLC7A11 expression was analyzed by reverse transcription-quantitative PCR (RT-qPCR), Western blot assay, and immunohistochemistry (IHC). The activation status of the phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (TOR) pathway was determined by Western blotting. RESULTS: Tan IIA suppressed CRC proliferation in a dose-dependent manner. Moreover, Tan IIA inhibited SLC7A11 expression in OUMS23 cells and tumor tissues. Functional assays showed that Tan IIA induces CRC apoptosis, ferroptosis, and ROS release in intracellular and tumor tissues, while SLC7A11 plasmid transfection reverses these effects. Furthermore, SLC7A11 plasmid reversed the effects of Tan IIA on tumor volume and weight in CRC subcutaneous tumors. Further experiments revealed that SLC7A11 plasmid abolished the effects of Tan IIA on the PI3K/AKT/mTOR pathway, as confirmed by increased phospho (p)-AKT and p-mTOR expression, as well as increased p-AKT/AKT and p-mTOR/ mTOR ratios. CONCLUSION: Tan IIA induces ferroptosis in CRC by suppressing SLC7A11 expression through the PI3K/AKT/mTOR pathway. Therefore, Tan IIA may be an effective therapeutic agent in the treatment of CRC.