Isogarcinol Reduces MARS Levels and Deactivates the PI3K/AKT Pathway to Suppress the Malignant Properties of Breast Cancer Cells

Natural products and their extracts are increasingly considered valuable sources for small-molecule anti-cancer drugs. This study investigates the biological impacts of isogarcinol (ISO) on breast Cancer (BC) cells and delves into the underlying mechanisms. In vitro, treatment of ISO at 13 μM substantially reduced the viability, proliferation, and mobility of BC. In vivo, ISO treatment at 5, 10, and 15 mg/kg reduced the tumorigenic activity of MDA-MB-231 cells and decreased the levels of Ki-67 and CD31. ISO exerted tumor suppressive effects by reducing the protein level of methionyl-tRNA synthetase (MARS), as the MARS restoration reversed the trends induced by ISO. Phosphorylation levels of phosphatidyl inositol 3 (PI3K) and protein kinase B (Akt) in BC cells were reduced by ISO but restored by MARS. In the presence of MARS upregulation, further treatment of Alpelisib, a suppressor of the PI3K/Akt pathway, suppressed the malignant properties of BC cells. Collectively, these results demonstrate that ISO curbs the malignant behavior of BC cells by reducing the MARS protein level and deactivating the PI3K/Akt pathway. ISO may be considered a promising regimen for the management of BC.

Breast cancer; Isogarcinol; MARS; PI3K/AKT signaling pathway; Xenograft tumors.