Mitochondria and Cancer: The Trigger Becomes the Treatment

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Once considered the cause of cancer, a tiny organelle known as the “powerhouse of the cell” may soon spawn a new treatment.

In 1955, Otto Warburg, recipient of the 1931 Nobel Prize for Medicine or Physiology, attributed cancer to damage to the mitochondria, tiny structures within each cell that are involved in energy production, the manufacture of ATP. Because of irreversible damage to the mitochondria, he argued, tumor cells shifted from respiration to fermentation, a much less efficient method for producing ATP.

“What was formerly only qualitative has now become quantitative,” Warburg said during a Stuttgart lecture reprinted by Science. “What was formerly only probable has now become certain. The era in which the fermentation of cancer cells or its importance could be disputed is over, and no one today can doubt that we understand the origin of cancer cells if we know how their large fermentation originates.”

With those confident words, Warberg hoped to put an end to disputes about the many potential causes of cancer. “I should like to add, as a further argument,” he continued, “the fact that there is no alternative today… From this point of view, mutation and carcinogenic agents are not alternatives, but empty words.”

As new information became available, the words mutation and carcinogenic agents were gradually reinflated and the notion of mitochondrial damage as the root cause of all cancers lost favor. Interest in mitochondria shifted from oncologists to scientists interested in liver or muscle biology, especially cardiologists studying heart muscle.

But Stephen L. Archer, the Harold Hines Jr. Professor of Medicine at the University of Chicago Medicine, a cardiologist specializing in pulmonary hypertension, and Jalees Rehman, a German scientist who worked with Archer, got interested all over again in studying mitochondria after reading some of Warburg’s historical papers. Instead of causing cancer, they wondered, could mitochondria provide a target for cancer therapy?

Within each cell, mitochondria are perpetually splitting in two, a process called fission, and merging back into one, called fusion. Before a cell can divide, the mitochondria must increase their numbers through fission and separate into two piles, one for each cell.

This makes them a promising new target for cancer therapy. By manipulating two of the biochemical signals that regulate the numbers of mitochondria in cells, the researchers found they could shrink human lung cancers transplanted into mice, a discovery they reported in February in the journal FASEB.

By tipping the balance toward fusion and away from fission in rapidly dividing cancer cells, Archer and colleagues were able to dramatically reduce cell division and prevent the rapid cell proliferation that is a hallmark of cancer growth. Increasing production of the signal that promotes fusion caused tumors to shrink to one-third of their original size. Treatment with a molecule that inhibits fission reduced tumor size by more than half.

“By boosting the fusion signal or blocking the fission signal we were able to tip the balance the other way, reducing cancer cell growth and increasing cell death,” said Archer, senior author of the study. “We believe this provides a promising new approach to cancer treatment.”

“This could be a potential new Achilles’ heel for cancer cells,” said lead author, Rehman, now an associate professor of medicine and pharmacology at the University of Illinois at Chicago. “Many anticancer drugs target cell division. Our work shifts the focus to a distinct but necessary step: mitochondrial division. The cell division cycle comes to a halt if the mitochondria are prevented from dividing. This new therapy may be especially useful in cancers which become resistant to conventional chemotherapy that directly targets the cycle.”

The researchers found that the mitochondrial networks within several different lung cancer cell lines were highly fragmented, compared to normal lung cells. Cancer cells had low levels of mitofusin-2 (Mfn-2), a protein that promotes fusion by tethering adjacent mitochondria, and high levels of dynamin-related protein (Drp-1), which initiates fission by encircling the organelle and squeezing it into two discrete fragments. The Drp-1 in cancer cells also tended to be in its most active form.

Although the authors identify mitochondrial fission as a potential therapeutic target in lung cancer, “this is not a cure,” Archer emphasized. The treatment drastically reduced tumor size but the tumors did not completely disappear. They continued to use high levels of glucose as fuel, a hallmark of cancer metabolism. “This remnant could be either a central cluster of cancer stem cells,” Archer said, “or an inflammatory response, the immune system infiltrating the tumor.”

The substances used to block fusion are commercially available for research purposes, but they have not been tested in humans.

“Inhibiting mitochondrial fission,” Archer said, “did not show any significant toxicity in mice or rats, so we are quite optimistic that our findings can lead to the development of novel, clinically feasible therapies.”

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Rehman, J., Zhang, H., Toth, P., Zhang, Y., Marsboom, G., Hong, Z., Salgia, R., Husain, A., Wietholt, C., & Archer, S. (2012). Inhibition of mitochondrial fission prevents cell cycle progression in lung cancer The FASEB Journal DOI: 10.1096/fj.11-196543

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