Researchers at the Karolinska Institutet, Sweden, have found a connection between low mitochondrial content and resistance to medications for deadly kidney cancer. The cancer cells responded to the treatment when they increased the mitochondrial content. Their research increases the possibility of more cancer treatments.
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| Image Credits: Genengnews |
What is the role of mitochondria in cancer?
Mitochondria are cell organelles that use oxygen to generate energy for the cell. It also plays an important role in cancer. Many cancer cells can survive without mitochondria, but they cannot grow without forming new strands of DNA in which mitochondria play a major role. As mitochondria use most of the oxygen for energy production, it is still unknown how they adjust in a low-oxygen environment and are linked to resistance to kidney cancer drugs.
What happens when VHL is mutated?
von Hippel-Lindau (VHL) is a part of a cell’s oxygen detection system. It is a gene that protects healthy cells from becoming cancerous. VHL gene’s protein breaks down another protein called HIF (Hypoxia-Inducible Factor). When VHL is mutated, HIF accumulates, as a result, a condition arises where cells react as if there is no oxygen despite oxygen being available. This is known as VHL syndrome. The syndrome increases the risks of both malignant and benign tumours. Kidney cancer caused by the VHL syndrome has a poor prognosis, with a 12 percent five-year survival rate.
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| Image Credits: Newscientist |
How did researchers overcome drug resistance?
The research team studied the protein content of cancerous cells from patients with variants of VHL syndrome and compared this to another group of patients having VHL mutation called Chuvash. This mutation is involved in hypoxia-sensing disorders without any tumour development. Patients with Chuvash VHL mutation had normal mitochondrial content in their cells, while patients with VHL syndrome had few mitochondria.
Researchers used a mitochondrial protease (enzymes responsible for the breakdown of mitochondria) inhibitor called LONP1 to increase the mitochondrial content in VHL-related kidney cancer cells. This inhibitor makes them susceptible to the cancer drug sorafenib.
As the mitochondrial content increases, the cells that were resistant to the cancer drugs were now found to respond to it. The researchers used this treatment approach in mice and discovered that it reduced tumour growth.
“We hope that this new knowledge will pave the way for more specific LONP1 protease inhibitors to treat VHL-related clear cell kidney cancer,” said Shuijie Li, a postdoctoral researcher at the Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet. “Our finding can be linked to all VHL syndromic cancers, such as the neuroendocrine tumours pheochromocytoma and paraganglioma, and not just kidney cancer.”
The detailed research has been published in the journal Nature Metabolism.
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