Caveolin-1 signaling-driven mitochondrial fission and cytoskeleton remodeling promotes breast cancer migration

Mitochondria are highly dynamic organelles that constantly divide and fuse to maintain their proper structure and function. Cancer cells are often accompanied by an imbalance of mitochondrial fusion and fission, cancer progression is greatly affected by this imbalance. Here, we found that high-metastatic breast cancer MDA-MB- 231 cells possess higher caveolin-1 (Cav-1) expression compared with low-metastatic breast cancer MCF-7 cells or normal breast epithelial MCF-10A cells. Downregulation of Cav-1 decreases the migratory and inva- sive abilities of MDA-MB-231 cells. Our results further demonstrated that downregulation of Cav-1 facilitated DRP1 and MFN2 to translocate to mitochondria, increasing the inhibitory phosphorylation level of DRP1 at Ser637 by protein kinase A (PKA), resulting in mitochondria elongation. We also showed that downregulation of Cav-1 significantly reduced the Rac1 activity by affecting intracellular reactive oxygen species (ROS) generation, which then inhibited F-actin formation. Based on these findings, we proposed that Cav-1 mediated mitochondrial fission-affected intracellular ROS generation and activated Rho GTPases, leading to F-actin-dependent formation of lamellipodia and promotion of breast cancer motility.

Automated summary

Mitochondrial dynamics play a crucial role in cancer progression, and an imbalance of mitochondrial fusion and fission can greatly affect cancer cell behavior. This study found that the expression of Cav-1 is higher in highly metastatic breast cancer cells compared to low-metastatic or normal breast cells. Downregulation of Cav-1 reduces the migratory and invasive abilities of breast cancer cells by affecting mitochondrial dynamics and intracellular ROS generation. These findings suggest that Cav-1 may be a potential target for inhibiting breast cancer metastasis.