SHIP2 Silencing Enhances Erastin Cytotoxicity in MDA-MB-231 Breast Cancer Cell Line

Background: Breast cancer (BC) is a serious health risk to women worldwide. Triple-negative breast cancer (TNBC) is a highly heterogeneous type of breast cancer that is highly malignant, recurrent, and invasive. Despite cancer treatment having developed rapidly in the past decades, TNBC is still having challenges. Erastin is an inducer of ferroptosis and inhibits tumor cell growth, thus making it a promising strategy for cancer therapy. The SH2-containing 5´ inositol phosphatase 2 (SHIP2) is overexpressed in BC, where it is associated with poor prognosis. Objective: To address the effect of erastin, SHIP2 silencing, and the combination of both on the viability of MDA-MB-231 BC cells and the impact on the protein kinase B (Akt)/mechanistic target of rapamycin (mTOR) pathway. Methods: MDA-MB-231 BC cells were cultured in Dulbecco’s modified Eagle’s medium (DMEM) and treated with erastin, SHIP2-siRNA, and their combination. Cell viability was assessed by 4,5-dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide (MTT) assay. Western blot was used to estimate the levels of phospho-Akt and p70 ribosomal protein S6 kinase (p70S6k). Results: The results showed that each of erastin, SHIP2-siRNA, and their combination resulted in growth inhibition of MDA-MB-231 cells and suppressed phospho-Akt but not p70S6K. Conclusions: SHIP2 silencing enhanced the cytotoxicity of erastin in MDA-MB-231 BC cells. Akt, but not mTOR, was involved in the signaling pathway of erastin and SHIP2-siRNA. The combination of both treatments has shown enhanced suppression of phospho-Akt. The results indicate that the combination of erastin and SHIP2-siRNA gives a promising strategy for the treatment of TNBC.