Abstract
Triple-negative breast cancer (TNBC) subtype is among the most aggressive cancers with the worst prognosis and least therapeutic targetability while being more likely to spread and recur. Cancer transformations profoundly alter cellular metabolism by increasing glucose consumption via glycolysis to support tumorigenesis. Here we confirm that relative to ER-positive cells (MCF7), TNBC cells (MBA-MD-231) rely more on glycolysis thus providing a rationale to target these cells with glycolytic inhibitors. Indeed, iodoacetate (IA), an effective GAPDH inhibitor, caused about 70% drop in MDA-MB-231 cell viability at 20 μM while 40 μM IA was needed to decrease MCF7 cell viability only by 30% within 4 hours of treatment. However, the triple negative cells showed strong ability to recover after 24 h whereas MCF7 cells were completely eliminated at concentrations <10 μM. To understand the mechanism of MDA-MB-231 cell survival, we studied metabolic modulations associated with acute and extended treatment with IA. The resilient TNBC cell population showed a significantly greater count of cells with active mitochondria, lower apoptotic markers, normal cell cycle regulations, moderately lowered ROS, but increased mRNA levels of p27 and PARP1; all compatible with enhanced cell survival. Our results highlight an interplay between PARP and mitochondrial oxidative phosphorylation in TNBC that comes into play in response to glycolytic disruption. In the light of these findings, we suggest that combined treatment with PARP and mitochondrial inhibitors may provide novel therapeutic strategy against TNBC.
Highlights
Breast cancer represents a major cause of death among women worldwide with more than a million new cases and hundreds of thousands deaths each year[1]
To explore the functional differences of different breast cell types, we used the Seahorse XF24 Flux Analyzer (Agilent, Germany) to profile oxidative phosphorylation as well as glycolysis in the hormone-responsive MCF7 and the triple-negative MDA-MB-231 cell lines, both accounted as the most commonly used BC cell line models (Fig. 1). Both mitochondrial- and glycolytic-stress assays were carried out using selective substrates/inhibitors of different metabolic states while measuring both oxygen consumption rate “Oxygen consumption rate (OCR)” and extracellular acidification rate “ECAR”
The natural question that arises from these observations is how Triple-negative breast cancer (TNBC) cells handle the long-term bioenergetic deprivation induced by IA treatment? We have shown in Fig. 1(D–H) that instantaneous addition of IA disrupts glycolysis completely in both cell types while moderately enhancing mitochondrial oxygen consumption especially in MCF7 cells
Summary
Breast cancer represents a major cause of death among women worldwide with more than a million new cases and hundreds of thousands deaths each year[1]. An altered metabolic phenotype known as Warburg effect has been described in cancer cells where an intense increase in glucose uptake through enhancement of glycolytic activity and dramatic lactate production even when oxygen supply is not scarce. This was consistent with diminished mitochondrial respiration despite the presence of high oxygen concentration[9]. It was reported that, when compared to hormone responsive cells, TNBC cells exhibit metabolic characteristics manifested by high glycolytic activity and low mitochondrial oxidative phosphorylation (OXPHOS)[12] We hypothesized that such metabolic phenotype in TNBC cells may render them highly sensitive to glycolytic inhibition opening a window for metabolic interventions targeting TNBCs. Iodoacetate is reported as a potent inhibitor of glycolysis. These criteria encouraged us to explore and revive the potential of iodoacetate as a simple and inexpensive drug candidate for specific targeting of breast malignancies
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