Researchers may have come across a novel treatment target to treat the rare but aggressive cancer adrenocortical carcinoma (ACC), according to a study recently published in Endocrinology.
The researchers, led by Wiebke Arlt and Paul A. Foster, both of the University of Birmingham in the United Kingdom, write that the mitochondrial NADPH generator Nicotinamide Nucleotide Transhydrogenase (NNT) plays a central role within mitochondrial antioxidant pathways, protecting cells from oxidative stress, and mutations that inactivate NNT cause congenital adrenal insufficiency. “Intriguingly,” the authors write, “despite the key role of NNT in preserving cellular redox balance and its ubiquitous expression, the adrenal glands are the only affected organ in most patients; this observation suggests a selective sensitivity of the adrenal glands to NNT loss.”
The team hypothesized that if they silenced NNT in ACC cells, it would impair the ACC cells’ antioxidant capacity and lead to progressive accumulation of reactive oxygen species (ROS), molecular mediators of oxidative stress. This would in turn induce oxidative toxicity and eventually trigger cellular apoptosis. They transiently knocked down NNT in ACC cells and found that “this manipulation increased intracellular levels of oxidative stress; this resulted in a pronounced suppression of cell proliferation and higher apoptotic rates, as well as sensitization of cells to chemically induced oxidative stress,” the authors write.
First author and final-year PhD student Vasileios Chortis then generated a stable NNT knockdown model to see what would happen in the long term when silencing NNT in the same cell line. The ACC cells adapted to chronic NNT knockdown and restored their oxidative stress resilience and redox balance, which abrogated the early impact of NNT loss. This was also associated with an increase in oxygen consumption. The researchers were able to observe these pathways through RNA sequencing, during which they observed an up-regulation of genes involved in protein folding and identifying and degrading damaged proteins. Purine and pyrimidine metabolism was activated in these cells, and ribosomal genes were up-regulated. The authors write that “these findings hint at increased protein turnover, involving degradation of damaged protein and acceleration of new protein synthesis. This may represent a key compensatory mechanism against oxidative stress, achieving the timely removal and replacement of irrevocably damaged (oxidized) proteins.”
“Taken together,” the authors conclude, “we show that NNT silencing can induce cytotoxicity and impede cell growth in adrenocortical carcinoma cells, as well as sensitize them to chemically induced oxidative stress. Moreover, we have demonstrated how the plasticity of ACC cells can lead to the development of a compensatory molecular response with time and described how changes in polyamine metabolism and [endoplasmic reticulum] protein processing are involved in this process.”