Mitochondria may be a new target for cancer therapy. Manipulation of two biochemical signals that regulate the numbers of mitochondria in cells could shrink human lung cancers transplanted into mice, according to a study by the University of Chicago Medicine.
Within each cell, mitochondria are constantly 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.
By reversing an imbalance of the signals that regulate fusion and fission in rapidly dividing cancer cells, researchers were able to dramatically reduce cell division, therefore preventing rapid cell proliferation. Increasing production of the signal that promotes mitochondrial 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.
“We found that human lung cancer cell lines have an imbalance of signals that tilts them towards mitochondrial fission,” says Stephen L. Archer, MD, the Harold Hines Jr. Professor of Medicine at the University of Chicago Medicine. “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.”
“Many anticancer drugs target cell division. Our work shifts the focus to a distinct but necessary step: mitochondrial division,” says Jalees Rehman, MD, an associate professor of medicine and pharmacology at the University of Illinois at Chicago. “The cell division cycle comes to a halt if the mitochondria are prevented from dividing. This therapy may be 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.
The researchers tested several ways to enhance fusion and restore the mitochondrial network, both in cell culture and in animal models. They used gene therapy to increase the expression of Mfn-2, injected a small molecule (mdivi-1) that inhibits Drp-1, and used genetic techniques to block the production of Drp-1. All three interventions reduced mitochondrial fragmentation, increased networking, and reduced cancer cell growth.
The treatment 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 that can be seen on PET scans. “This remnant could be either a central cluster of cancer stem cells,” Archer says, “or an inflammatory response, the immune system infiltrating the tumor.”
Inhibiting mitochondrial fission did not show any significant toxicity in mice or rats. The substances used to block fusion have not been tested in humans.
The research was reported in FASEB.
Release Date: Feb. 21, 2012
Source: University of Chicago Medicine