Ganoderic acid a exerts antitumor activity against MDA-MB-231 human breast cancer cells by inhibiting the Janus kinase 2/signal transducer and activator of transcription 3 signaling pathway

Abstract

Breast cancer is a common malignant tumor among females, with triple-negative breast cancer being an important type accounting for 15-20% of all breast cancer cases. Triple-negative breast cancer is one of the most aggressive types of cancer without standard adjuvant chemotherapy. Ganoderic acid A (GA-A) is one of the major bioactive Ganoderma triterpenoids isolated from Ganoderma, which are recognized for their preventative and therapeutic effects. In the present study, the antineoplastic effect of GA-A on human breast cancer was investigated and the pro-apoptotic function of Janus kinase (JAK)2 and signal transducer and activator of transcription (STAT)3 on the function of GA-A was revealed. GA-A treatment inhibited the invasion of MDA-MB-231 cells. In addition, GA-A exhibited significant antitumor activity by enhancing the apoptotic index and reactive oxygen species production. In the present study, GA-A was identified to directly inhibit JAK2 phosphorylation and STAT3 downstream activation. In addition, GA-A suppressed STAT3 target gene expression, including B cell lymphoma-extra-large and Myeloid cell leukemia 1, resulting in elevated levels of proteins associated with mitochondrial apoptosis in addition to inhibitors of cyclin-dependent kinase. GA-A, in combination with AG490, a JAK2/STAT3 inhibitor, further decreased MDA-MB-231 cell viability. In conclusion, GA-A treatment inhibited breast cancer cell viability via JAK2/STAT3 downregulation and may regulate associated targets to serve an anti-MDA-MB-231 role, including mitochondrial apoptosis and regulating the expression of cell-cycle-associated factors.