Abstract 467: Mitochondrial dynamics regulates migration and invasion of breast cancer cells

Abstract

Abstract Mitochondrial structure is dynamically regulated by fusion and fission events that are essential for maintaining physiological functions of cells. Although dysfunction of mitochondria has been implicated in tumorigenesis, little is known about the roles of mitochondrial dynamics in metastasis, the major cause of cancer death. In the present study, we found that mitochondria were more fragmented in metastatic breast cancer cells that express higher levels of mitochondrial fission protein dynamin-related protein 1 (Drp1) and less mitochondrial fusion protein 1 (Mfn1). Silence of Drp1 or overexpression of Mfn1 resulted in mitochondria elongation and significantly suppressed metastatic abilities of breast cancer cells. In contrast, silence of Mfn proteins led to mitochondrial fragmentation and enhanced metastatic abilities of breast cancer cells. Interestingly, these manipulations of mitochondrial dynamics had no significant effects on overall mitochondrial bioenergetics but altered the subcellular distribution of mitochondria in breast cancer cells. Silence of Drp1 or overexpression of Mfn1 inhibited lamellipodia formation, a key step for cancer metastasis, and suppressed chemoattractant-induced recruitment of mitochondria to lamellipodial regions. Conversely, silence of Mfn proteins caused accumulation of more mitochondria in lamollipodia regions with higher mitochondrial membrane potential, an indication of higher ATP synthesis. Treatment with the ATP uncoupling agent m-chlorophenylhydrazone (CCCP) or mitochondrial ATP synthesis inhibitor oligomycin A caused disappearance of lamellipodia and decreased breast cancer cell migration and invasion. Together, our findings show a new mechanism for regulation of cancer cell migration and invasion by mitochondrial dynamics. Thus targeting mitochondrial dynamics may provide a novel strategy for suppressing breast cancer metastasis. This work was supported by the National Institutes of Health (CA125661), State of Nebraska Research Fund (Grant LB595), the National Natural Science Foundation of China (31100973) and the National Basic Research Program (2010CB833701, 2012CB934003). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 467. doi:1538-7445.AM2012-467