Thursday, 10 March 2016

Selective Vulnerability of Cancer Cells by Inhibition of Ca2+ Transfer from Endoplasmic Reticulum to Mitochondria

http://www.sciencedirect.com/science/article/pii/S2211124716301334

César Cárdenas, Marioly Müller, Andrew McNeal, Alenka Lovy, Fabian Jaňa, Galdo Bustos, Felix Urra, Natalia Smith, Jordi Molgó, J. Alan Diehl, Todd W. Ridky, J. Kevin Foskett

Mitochondria are often found to be tethered to another organelle of the cell, called the endoplasmic reticulum (ER). The ER releases calcium into the mitochondria, which stimulates energy metabolism by increasing the rate of several catalysts in the metabolic network. A basal level of calcium release is necessary for mitochondrial ATP production in many cell types. Without this, cells tend to start recycling themselves through autophagy, as a survival mechanism.

In this study, the authors probe the difference in response to normal and cancer cells, to blocking calcium release (using the drug XeB, as well as genetic knockdown of the gene InsP3R) from the ER to mitochondria. The authors compared the cell death response of non-tumourigenic MCF10A cells to three tumorigenic cell lines (MCF7, T47D and HS578T). At 5uM XeB, the authors find that breast tumour cell lines experienced significant cell death (43, 53 and 22%) whereas normal cells were less sensitive to the drug (5% cell death). Similar effect sizes were seen in prostate cancer cells, at the same drug concentration. It was also the case that XeB did not induce large cell death in primary human fibroblasts, when compared to transformed cells.

The authors found that providing the tumour cells with additional pyruvate rescued their proliferation rate. Calcium stimulates the enzyme pyruvate dehydrogenase, which takes pyruvate from glycolysis and converts it into acetyl-coa, for use in mitochondrial metabolism. Therefore it is reasonable to conclude that providing additional pyruvate pushes flux through the network, to compensate for lower enzymatic activity (by mass-action kinetics).

The authors hypothesized that nucleoside supplementation may also rescue the effect of calcium import inhibition, since mitochondrial metabolism is intertwined with nucleoside synthesis (a necessity for DNA synthesis). Indeed, the authors found that nucleoside supplementation ameliorated cytotoxicity by ~50%. This indicates that nucleoside production of mitochondria is more important than their energy production, in this model. The authors show mechanistically that, when cancer cells are blocked in calcium uptake, they progress through the cell cycle normally, but their progression into mitosis results in necrotic cell death. In contrast, normal cells halt their cell cycle at G1 phase.



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