Blocking Calcium Transfer May Selectively Kill Cancer Cells
, by NCI Staff
A new study shows that blocking the transfer of calcium ions (Ca2+) into mitochondria is toxic to cancer cells and impairs growth of tumors in mice, while sparing normal cells.
All cells use calcium ions as signaling agents to regulate metabolism and other cellular functions. Blocking the flow of calcium into mitochondria, which are the chief producers of energy-rich ATP molecules in cells, created an energy “crisis” from which normal cells could recover but cancer cells could not, the study showed.
The new findings “[suggest] that mitochondrial addiction to calcium is a novel feature of cancer cells that could be exploited to develop new, targeted cancer therapies,” senior study author J. Kevin Foskett, Ph.D., of the University of Pennsylvania said in a news release.
Results of the study were published in Cell Reports on March 3.
A Cellular Energy Crisis
Mitochondria are compartments (organelles) within cells that break down nutrients to produce energy in the form of ATP, which cells use to power biochemical reactions. Previous work by Dr. Foskett’s lab showed that calcium ions are constantly being shuttled to the mitochondria from another cellular compartment, the endoplasmic reticulum , or ER. This ongoing transfer of calcium between the ER and mitochondria helps maintain ATP production through a metabolic process called oxidative phosphorylation.
Specialized receptor proteins—called InsP3Rs for short—form channels that span the ER membrane and allow calcium to flow out in a controlled fashion. Calcium ions released from the ER then move into the adjacent mitochondria.
Working with cell lines, the research team, co-led by César Cárdenas, Ph.D., of the University of Chile, used a compound found in sea sponges, called XeB, that inhibits InsP3Rs, impeding the flow of calcium from the ER to mitochondria. They examined the effects of XeB in human cancer cell lines derived from breast and prostate cancers, in human fibroblast cells that had been transformed into cancer cells, and in comparable normal cells.
When the flow of calcium into mitochondria was blocked by XeB, both the cancer cells and normal cells experienced a “bioenergetic crisis” that was marked by reduced ATP production and by other signs of slowed cell metabolism. Confirming previous work by Dr. Foskett’s lab, the normal cells survived this energy crisis by activating a mechanism known as autophagy. In autophagy, or “self-eating,” cells recycle cell components to maintain energy levels under conditions of starvation or stress. Cancer cells also activated autophagy when the flow of calcium was blocked, but the self-eating response was not enough to keep the cancer cells from dying.
Further experiments showed that blocking calcium transfer caused normal cells to stop dividing, which is an expected response when energy is in short supply. By contrast, cancer cells treated the same way continued to divide, but then underwent cell death during the last phase of cell division.
Using a mouse model of melanoma, the researchers also found that blocking InsP3R activity via a single injection of XeB reduced tumor size by nearly 60 percent in one day compared with untreated tumors. In another set of mouse experiments, treatment with XeB every other day for a week reduced melanoma tumor size by about 70 percent compared with untreated tumors in the same animal.
An Unexpected Therapeutic Target
“Our studies suggest the existence of completely unexpected new targets for which drugs could be developed to kill cancer cells specifically by targeting calcium release from the ER and calcium uptake by mitochondria,” Dr. Foskett said.
“This work and past work from other groups provides compelling evidence that calcium signaling is altered in cancer cells,” said Gregory Monteith, Ph.D., of the University of Queensland, Australia, who was not involved in the study.
“In the specific case of calcium transfer from the ER to the mitochondria, we now need to develop a better understanding of what proteins in this pathway could be pharmacologically targeted and ensure that, when modulated, this will not have substantial effects in other cell types that might lead to prohibitive side effects," Dr. Monteith said.
Dr. Foskett and his colleagues are working to devise cell line-based high-throughput assays (laboratory tests) to screen potential drugs that could hit one or more of these new targets. “We also plan to partner with cancer biologists to develop some better animal models to test our hypothesis [and] move it forward into different kinds of cancers, to see whether what we’ve seen in cell lines and in one type of tumor…holds up in more robust models.”
“Understanding how inter-organelle communication patterns are either maintained or altered in cancer cells is an emerging area in the cancer biology field,” said Michael Espey, Ph.D., of the Cancer Cell Biology Branch in NCI’s Division of Cancer Biology. “The finding that cancer cells become overtly reliant on ER-to-mitochondria flow of calcium ions opens up new avenues for designing treatments that exploit this vulnerability.”