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Pancreatic ductal adenocarcinoma (PDAC) represents the most common form of pancreatic cancer with rising incidence in developing countries and overall 5-year survival rates of less than 5%. The most frequent mutations in PDAC are gain-of-function mutations in KRAS as well as loss-of-function mutations in p53. Both mutations have severe impacts on the metabolism of tumor cells. Many of these metabolic changes are mediated by transporters or channels that regulate the exchange of metabolites and ions between the intracellular compartment and the tumor microenvironment. In the study presented here, our goal was to identify novel transporters or channels that regulate oxidative phosphorylation (OxPhos) in PDAC in order to characterize novel potential drug targets for the treatment of these cancers. We set up a Seahorse Analyzer XF based siRNA screen and identified previously described as well as novel regulators of OxPhos. The siRNA that resulted in the greatest change in cellular oxygen consumption was targeting the KCNN4 gene, which encodes for the Ca2+-sensitive K+ channel KCa3.1. This channel has not previously been reported to regulate OxPhos. Knock-down experiments as well as the use of a small molecule inhibitor confirmed its role in regulating oxygen consumption, ATP production and cellular proliferation. Furthermore, PDAC cell lines sensitive to KCa3.1 inhibition were shown to express the channel protein in the plasma membrane as well as in the mitochondria. These differences in the localization of KCa3.1 channels as well as differences in the regulation of cellular metabolism might offer opportunities for targeted therapy in subsets of PDAC. [ABSTRACT FROM AUTHOR]

Cancer cells are characterized by an increase in the rate of reactive oxygen species (ROS) production and an altered redox environment compared to normal cells. Furthermore, redox regulation and redox signaling play a key role in tumorigenesis and in the response to cancer therapeutics. ROS have contradictory roles in tumorigenesis, which has important implications for the development of potential anticancer therapies that aim to modulate cellular redox levels. ROS play a causal role in tumor development and progression by inducing DNA mutations, genomic instability, and aberrant pro-tumorigenic signaling. On the other hand, high levels of ROS can also be toxic to cancer cells and can potentially induce cell death. To balance the state of oxidative stress, cancer cells increase their antioxidant capacity, which strongly suggests that high ROS levels have the potential to actually block tumorigenesis. This fact makes pro-oxidant cancer therapy an interesting area of study. In this review, we discuss the controversial role of ROS in tumorigenesis and especially elaborate on the advantages of targeting ROS scavengers, hence the antioxidant capacity of cancer cells, and how this can be utilized for cancer therapeutics. [ABSTRACT FROM AUTHOR]