Blocking Transfer of Calcium to Cell’s Powerhouse Selectively Kills Cancer Cells

cancer cells
Inhibition of low-level endoplasmic reticulum-to-mitochondria calcium ion transfer is toxic, specifically to cancer cells.

Inhibiting the transfer of calcium ions into the cell’s powerhouse is specifically toxic to cancer cells, according to an article published this week in Cell Reports by researchers from the Perelman School of Medicine at the University of Pennsylvania.

“This suggests that calcium addiction by mitochondria is a novel feature of cancer cells,” said senior author Kevin Foskett, PhD, chair of the department of Physiology. “We were surprised by this unexpected dependency on calcium transfer to the mitochondria for the survival of cancer cells.” These findings suggest an entirely new target for cancer drugs.

Special proteins, called IP3Rs for short, are a common family of calcium ion channels that span the membranes of the endoplasmic reticulum (ER), a network of small tubes inside every cell that involved in making proteins and lipids. Calcium ions from the ER are released through the channel and regulate many cell functions, including cell metabolism. This is achieved primarily by supplying calcium to mitochondria where it stimulates the production of ATP to power cell functions.

Most healthy cells in the body rely on a complicated process called oxidative phosphorylation to produce ATP. Knowledge about how ATP is produced by the cell’s mitochondria, the energy storehouse, is important for understanding normal cell metabolism, which will provides insights into abnormal cell metabolism, as in the case of cancer.

The Foskett lab showed in a 2010 Cell article that a fundamental control system regulating ATP is an ongoing shuttling of calcium ions to the mitochondria from the ER, and this maintains normal levels of ATP in a wide variety of cell types. They also found that in the absence of this calcium ion transfer, ATP levels fall and a process called autophagy, literally self-eating, is induced so the cell can survive.

In all cell types that the team examined, inhibiting the uptake of calcium ions by mitochondria induced a bioenergetic crisis that reprogrammed the cells’ metabolism in a way that is reminiscent of nutrient starvation, despite nutrient availability and uptake by the cell. A hallmark of cancer cells is re-programming their own metabolism, even when nutrients are available to provide the building blocks necessary for cancer cells to divide and grow so prolifically. As such, all major tumor suppressors and oncogenes have connections with metabolic pathways.