Mst1-Hippo pathway triggers breast cancer apoptosis via inducing mitochondrial fragmentation in a manner dependent on JNK-Drp1 axis.

ABSTRACT

BACKGROUND AND OBJECTIVE: Mst1-Hippo pathway and mitochondrial fragmentation participate in the progression of several types of cancers. However, their roles in breast cancer requires investigation. The aim of our study is to determine whether Mst1 overexpression regulates the viability of breast cancer cells via modulating mitochondrial fragmentation. MATERIALS AND METHODS: TUNEL staining, MTT assay and Western blotting were used to detect cancer cell death. Adenovirus-loaded Mst1 was transfected into cells to overexpress Mst1. Mitochondrial fragmentation was observed via immunofluorescence staining and Western blotting. Pathway blocker was used to detect whether Mst1 modulated cell death and mitochondrial fragmentation via JNK signaling pathway. RESULTS: Our data showed that Mst1 overexpression promoted breast cancer cell death in a manner dependent on mitochondrial apoptosis. Mitochondrial oxidative stress, energy metabolism disorder, mitochondrial cyt-c liberation and mitochondrial apoptosis activation were observed after Mst1 overexpression. Furthermore, we demonstrated that Mst1 overexpression activated mitochondrial stress via triggering Drp1-related mitochondrial fragmentation, and that inhibition of Drp1-related mitochondrial fragmentation abrogated the proapoptotic effect of Mst1 overexpression on breast cancer cells. To this end, we found that Mst1 modulated Drp1 expression via the JNK signaling pathway, and that blockade of the JNK pathway attenuated mitochondrial stress and repressed apoptosis in Mst1-overexpressed cells. CONCLUSION: Altogether, our results identified a tumor suppressive role for Mst1 overexpression in breast cancer via activation of the JNK-Drp1 axis and subsequent initiation of fatal mitochondrial fragmentation. Given these findings, strategies to enhance Mst1 activity and elevate the JNK-Drp1-mitochondrial fragmentation cascade have clinical benefits for patients with breast cancer.