Penn Vet study links mitochondrial stress to cancer

For a normal cell to turn cancerous, it must undergo an array of molecular changes, many of which have yet to be identified, much less parsed. But new findings from a research group led by Narayan Avadhani, a scientist at the School of Veterinary Medicine, have nailed down the particulars of one molecular process that seems intimately tied to cancer progression.

The connection hinges on impaired function of mitochondria, the organelles contained in every cell that are responsible for manufacturing energy from glucose.

“Our study provides a rigorous demonstration of a link between mitochondrial function and nuclear gene expression,” says Avadhani, the Harriet Ellison Woodward Professor of Biochemistry. “Since we know that this type of signaling has a direct role in the early stages of cancer progression, the protein involved could be a very valuable target for alleviating this signaling and possibly cancer progression.”

Avadhani’s lab has spent years investigating the connection between mitochondrial dysfunction and cancer. In their new work, published in the journal Cell Discovery, he and colleagues zeroed in on one protein they had identified in earlier screens to be a likely player in translating mitochondrial stress to changes in nuclear DNA—changes associated with tumor growth.

Through a series of experiments, the researchers found that the protein hnRNPA2 activated the gene promoters of nuclear genes associated with stress. The activation was performed through an epigenetic process: hnRNPA2 transferred chemical chains known as acetyl-CoA groups onto a histone, helping to open up tightly packed DNA and allow it to be transcribed into RNA.

The team identified the specific sites on hnRNPA2 that bound acetyl groups. When they produced versions of hnRNPA2 with these sites mutated, the acetyl transfer activity was greatly reduced. Cells containing the mutant protein also had a reduced ability to invade—a necessity for tumor cells.

Researchers have discovered that compounds derived from the fruit Garcinia indica, commonly known as kokum, which grows on the west coast of India, can block enzymes like hnRNPA2 from transferring acetyl groups. And indeed, when the researchers exposed hnRNPA2 to these compounds and their derivatives, the enzyme’s activity was greatly diminished.

Looking ahead, the Penn Vet team hopes to work closely with researchers from India’s Jawaharlal Nehru Centre for Advanced Scientific Research to see if kokum-derived compounds may prove as effective anti-cancer agents.