Cancer cells defy the rules by which normal cells abide. They can divide
without cease, invade distant tissues and consume glucose at abnormal rates.
Now a study by University of Pennsylvania researchers implicates defects in
mitochondria, the energy-production centers of cells, as playing a key role in
the transition from normal to cancerous. When the Penn scientists disrupted a
key component of mitochondria, otherwise normal cells took on characteristics of
cancerous tumor cells.
The research is published in the journal Oncogene and was led by members of
the lab of Narayan G. Avadhani, the Harriet Ellison Woodward Professor of
Biochemistry in Penn's School of Veterinary Medicine's Department of Biomedical
Sciences, in collaboration with the lab of Hiroshi Nakagawa from the
Gastroenterology Division in Penn's Perelman School of Medicine. Satish
Srinivasan, a research investigator in Avadhani's lab, was the lead author.
Manti Guha, Dawei Dong and Gordon Ruthel of Penn Vet and Kelly A. Whelan of Penn
Medicine also contributed, along with Yasuto Uchikado and Shoji Natsugoe of
Japan's Kagoshima University.
In 1924, German biologist Otto Heinrich Warburg observed that cancerous
cells consumed glucose at a higher rate than normal cells and had defects in
their "grana," the organelles that are now known as mitochondria. He postulated
that the mitochondrial defects led to problems in the process by which the cell
produces energy, called oxidative phosphorylation, and that these defects
contributed to the cells becoming cancerous.
"The first part of the Warburg hypothesis has held up solidly in that most
proliferating tumors show high dependence on glucose as an energy source and
they release large amounts of lactic acid," Avadhani said. "But the second part,
about the defective mitochondrial function causing cells to be tumorigenic, has
been highly contentious."
To see whether the second part of Warburg's postulation was correct, the
Penn-led research team took cell lines from the skeleton, kidney, breast and
esophagus and used RNA molecules to silence the expression of select components
of the mitochondrias' cytochrome oxidase C, or CcO, a critical enzyme involved
in oxidative phosphorylation. CcO uses oxygen to make water and set up a
transmembrane potential that is used to synthesize ATP, the molecule used for
energy by the body's cells.
The biologists observed that disrupting only a single protein subunit of
cytochrome oxidase C led to major changes in the mitochondria and in the cells
themselves.
"These cells showed all the characteristics of cancer cells," Avadhani
said.
They displayed changes in their metabolism, becoming more reliant on
glucose and reducing their synthesis of ATP. Instead of conducting oxidative
phosphorylation, they largely switched over to conducting glycolysis, a less
efficient means of making ATP that is common in cancer cells.
The cells lost contact inhibition and gained an increased ability to invade
distant tissues, both "hallmarks of cancer cells," Avadhani noted. When they
were grown in a 3D medium, which closely mimics the natural environment in which
tumors grow in the body, the cells with disrupted mitochondria formed large,
long-lived colonies, akin to tumors.
The researchers also silenced cytochrome oxidase C subunits in an
already-tumorigenic breast and esophageal cancer cell lines.
"We found that the cells became even more invasive, heightening their
malignant potency," Srinivasan said.
Finally the Penn team looked at actual tumors from human patients and found
that the most oxygen-starved regions, which are common in tumors, contained
defective versions of cytochrome oxidase.
"That result alone couldn't tell us whether that was the cause or effect of
tumors, but our cell system clearly says that mitochondrial dysfunction is a
driving force in tumorigenesis," Avadhani said.
The researchers observed that disrupting CcO triggered the mitochondria to
activate a stress signal to the nucleus, akin to an "SOS" alerting the cell that
something is amiss. Avadhani and his colleagues had previously seen a similar
pathway activated in cells with depleted mitochondrial DNA, which is also linked
to cancer.
Building on these findings, Avadhani and members of his lab will examine
whether inhibiting components of this mitochondrial stress signaling pathway
might be a strategy for preventing cancer progression.
"We are targeting the signaling pathway, developing a lot of small
molecules and antibodies," Avadhani said. "Hopefully if you block the signaling
the cells will not go into the so called oncogenic mode and instead would simply
die."
In addition, they noted that looking for defects in cytochrome oxidase C
could be a biomarker for cancer screening.
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