Mitochondrial translocator protein modulates metabolism and pharmacologically induced apoptosis in breast cancer cells

Introduction

Dysfunctional mitochondria contribute to the onset of malignant transformation and growth. Molecules that regulate mitochondrial homeostasis are therefore the object of great attention to identify novel therapeutic strategies. The mitochondrial translocator protein (mTSPO) stands in a critical position for mitochondrial homeostasis and is involved in the physiology of breast cancer where it is overexpressed and positively associated with aggressiveness [1]. mTSPO ligands are therefore exploited for cancer imaging and chemotherapy, such as PK11195. mTSPO is associated with the voltage-dependent anion channels (VDACs), which regulate the metabolites' flux into mitochondria [2]. mTSPO expression is driven by the oncogene protein kinase Cε, suggesting a fundamental crosstalk for malignant transformation and uncontrolled proliferation. We hypothesized that mTSPO by regulating VDAC performance impinges on metabolism and pharmacologically induced cell death in breast cancer cells.

Results

In human breast adenocarcinoma MCF-7 and in cervical cancer cells (HeLa) we found, via imaging and luminescent-based approaches, that a decreased mTSPO/VDAC ratio of expression uperegulates mitochondrial Ca²⁺ uptake and ATP generation whilst reducing the rate of reactive oxygen species generation calling for a metabolic switch via an improvement of mitochondrial function. mTSPO suppression also impairs protein kinase Cε activation and facilitates Ca²⁺-dependent apoptosis triggered by C₂-ceramide. Nevertheless, mTSPO targeting with PK11195 - which impinges on Ca²⁺ homeostasis [3] - raises C₂-ceramide cell death in MCF-7 and in the more aggressive line of adenocarcinoma MDA10 - characterized by an increased mTSPO/VDAC ratio of expression.

Conclusions

The evidence proposes mTSPO as a neglected pathway in the cell signalling of breast cancer and paves the way for future studies to exploit mTSPO as a suitable prognostic marker and target for molecular chemotherapy.