Dynamin-related protein 1 is involved in micheliolide-induced breast cancer cell death

Abstract

Dynamin-related protein 1 (Drp1) is a newly discovered therapeutic target for tumor initiation, migration, proliferation, and chemosensitivity. Thus, therapeutic strategies that focus on targeting Drp1 and its related signaling pathway pave a new way to address the ineffectiveness of traditional cancer therapies. Micheliolide (MCL), a guaianolide sesquiterpene lactone, can selectively eradicate acute myeloid leukemia stem or progenitor cells. But the effect of MCL on the mitochondrial dynamics of cancer cells is still not well demonstrated. In this study, we show that MCL inhibited the growth of MCF-7 human breast cancer cells, accompanied by increased mitochondrial fission and upregulation of Drp1. The results obtained from overexpression experiments of wild or dominant-negative mutant type of Drp1 demonstrate that Drp1 is both necessary and sufficient to induce MDA-MB-231 and MCF-7 cell death. Furthermore, mitochondrial membrane potential decreased, whereas reactive oxygen species (ROS) generation, cytochrome c release, and PARP cleavage were enhanced after overexpression of Drp1 wild type. On the other hand, overexpression of Drp1-K38A (a dominant-negative mutant of Drp1) rescued cells from increased apoptosis, confirming the role of MCL-induced Drp1 in the observed apoptosis. Finally, MCL-induced Drp1-mediated cell death could be reversed by N-acetyl-l-cysteine (the ROS scavenger) in breast cancer cells. Taken together, the present study shows a novel role for Drp1 in MCL-induced breast cancer cell death, potentially through regulation of ROS–mitochondrial apoptotic pathway.