Inhibition of TRAP1 in the C-terminal domain influences mitochondria properties and breast cancer cell metabolism

Abstract

Breast cancers are characterized by complex energy metabolisms involving the Warburg effect but also mitochondria, although this area is not yet well understood. Tumor cells are particularly flexible by choosing oxidative phosphorylation (OXPHOS) or glycolysis depending on the needs and aggressiveness. Within the mitochondria, a HSP90-chaperone protein, TRAP1, exerts regulatory effects on several vital functions such as OXPHOS, production of reactive oxygen species and apoptosis by interacting with members of the respiratory chain or the mPTP. However, not all of its roles have yet been elucidated. Here, we propose to modulate TRAP1 functions using a mitochondriotropic molecule (containing triphenylphosphonium) targeting its C-terminal domain, 6BrCaQ-C₁₀-TPP, in breast tumor cells. Its blocks proliferation with no massive apoptosis, after 24 h of treatment, and induces dissipation of the mitochondrial membrane potential. 6BrCaQ-C₁₀-TPP also appears to modulate regulators of epithelial-mesenchymal transition (Snail and ZEB1) without a common response in all cell lines. Furthermore, the chaperone machinery is affected with a decrease of HSF1 and HSP70, but without degradation of HSP90 or TRAP1, while decreasing the levels of SDH-A and/or SDH-B, partner of TRAP1. Finally, short-term treatments (1 and 3 h) with 6BrCaQ-C₁₀-TPP modify energy metabolism by promoting glycolysis. In conclusion, modulation of TRAP1 on the C-terminal domain by 6BrCaQ-C₁₀-TPP exerts a cell-line dependent anti-tumor effect by modulating major mitochondrial functions in vitro. The differences between cell types need to be clarified. This study confirms that TRAP1 is a target of interest in breast cancer cells, but some of its functions still need to be elucidated.

Keywords: Breast cancer; Chaperone protein; Metabolism; Mitochondria.