Fuelling the calcium pumps in pancreatitis and pancreatic cancer

This seminar will focus on two related diseases; pancreatitis and pancreatic cancer, which are linked not least because pancreatitis is a major risk factor for pancreatic cancer, but also by altered metabolism and how this regulates cytosolic Ca²⁺ homeostasis. Central to this is the metabolic regulation of the ATP-driven plasma membrane Ca²⁺ pump (PMCA), which is a major focus of this talk.

During the first part of the talk I will show data showing that insulin, released endogenously from pancreatic β-cells of the pancreas, protects pancreatic acinar cells during both in vivo and cellular models of acute pancreatitis. Specifically, using two mechanistically distinct experimental models, pancreatitis was worse in Akita type-1 diabetic mice, in which insulin secretion is impaired, and PACIRKO mice, in which insulin receptors were specifically deleted in pancreatic acinar cells of adult mice. Moreover, in isolated acinar cells exogenous insulin markedly attenuated the ATP depletion, inhibition of the PMCA, cytotoxic Ca²⁺ overload and necrosis induced by pancreatitis-inducing agents. This was due to a switch from mitochondrial metabolism towards glycolysis which preserved ATP, and thus PMCA activity, even when mitochondria were impaired.

In the second part of the talk I will show how glycolytic ATP is critical for fuelling the PMCA in pancreatic cancer cells. Specifically, glycolytic inhibitors induce ATP depletion, inhibition of the PMCA, cytotoxic Ca²⁺ overload and necrosis, whereas mitochondrial inhibitors had no effect. Moreover, key oncogenic glycolytic enzymes associate with the plasma membrane where they provide a privileged ATP supply to the PMCA. This suggests that cutting off this privileged glycolytic ATP supply to the PMCA may represent a potential therapeutic strategy for selectively killing cancer cells while sparing healthy non-cancerous cells.

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