A new method could cure lethal cancer by restoring mitochondria count

Have we unlocked a new type of cancer treatment?
Ameya Paleja
3D illustration of cancer cells.
3D illustration of cancer cells.Dr_Microbe/iStock
  • Researchers in Sweden have successfully treated tumors in mice by increasing the number of mitochondria in the cells.
  • The team worked with VHL-induced kidney cancer cells and found that treating them with a protein called LONP1 makes them susceptible to the cancer drug sorafenib.
  • With mitochondrial numbers up, the cells that were earlier resistant to the cancer drug were now found to respond to it.

Researchers at the Karolinska Institutet in Sweden have successfully demonstrated treating tumors in mice after increasing the number of mitochondria in the cells. The tumors were previously resistant to cancer treatment.

Researchers around the world are trying different methods to treat cancer. While some aim to stop the cell division in tumors, others are working to enhance the abilities of the human immune system to detect and vanquish cancerous cells.

Work is also being done to understand how healthy cells turn cancerous and what can be done to stop them. The 2019 Nobel Prize in Physiology was awarded to scientists who studied how cells sense and adapt to oxygen availability. Central to the whole mechanism is a gene called von Hippel-Lindau (VHL).

The role of VHL in cancer

VHL is part of the oxygen detection system inside a cell. Under normal conditions, the protein produced by the VHL gene acts on another protein called HIF, However, if the VHL gene is mutated, its protein cannot act on HIF, and this results in a condition where cells behave as if oxygen is unavailable, even though it might be abundant. This is called VHL syndrome.

Studies have shown that VHL syndrome severely increases the risk of malignant as well as benign tumors. Kidney cancer induced by VHL syndrome has a poor prognosis, and only 12 percent of individuals affected by the disease survive beyond five years from the time of diagnosis.

Susanne Schlisio, an associate professor at the Department of Microbiology, Tumor and Cell Biology, and her team at the Karolinska Institutet studied the protein content of cancerous cells induced due to VHL syndrome and those in another group of individuals who also have a mutation in the VHL gene but at a different location. Called Chuvash, this other mutation also results in a lack of oxygen-like disorder but does not lead to tumor development.

The difference between the two was the number of mitochondria in the cells. While VHL syndrome resulted in low mitochondrial numbers, the Chuvash mutation did not drop the number of mitochondria in the cells. It is well known that mitochondria in the cells utilize oxygen to make energy. However, it is not understood how they adjust to low-oxygen environments and the role in play in the resistance to cancer treatments.

How regaining mitochondria numbers can help beat cancer?

Schilisio and her team worked with VHL-induced kidney cancer cells and found that treating them with a protein called LONP1 makes them susceptible to the cancer drug sorafenib. LONP1 is a mitochondrial protease inhibitor, which means it stops the enzymes that are responsible for the breakdown of mitochondria.

With mitochondrial numbers up once again, the cells that were earlier resistant to the cancer drug were now found to respond to it. The researchers used the treatment approach in mice models and found that it reduced tumor 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 in Schlisio’s team. “Our finding can be linked to all VHL syndromic cancers, such as the neuroendocrine tumors pheochromocytoma and paraganglioma, and not just kidney cancer."

The research findings were published in the journal Nature Metabolism.

Abstract

Mitochondria are the main consumers of oxygen within the cell. How mitochondria sense oxygen levels remains unknown. Here we show an oxygen-sensitive regulation of TFAM, an activator of mitochondrial transcription and replication, whose alteration is linked to tumours arising in the von Hippel–Lindau syndrome. TFAM is hydroxylated by EGLN3 and subsequently bound by the von Hippel–Lindau tumour-suppressor protein, which stabilizes TFAM by preventing mitochondrial proteolysis. Cells lacking wild-type VHL or in which EGLN3 is inactivated have reduced mitochondrial mass. Tumorigenic VHL variants leading to different clinical manifestations fail to bind hydroxylated TFAM. In contrast, cells harbouring the Chuvash polycythaemia VHLR200W mutation, involved in hypoxia-sensing disorders without tumour development, are capable of binding hydroxylated TFAM. Accordingly, VHL-related tumours, such as pheochromocytoma and renal cell carcinoma cells, display low mitochondrial content, suggesting that impaired mitochondrial biogenesis is linked to VHL tumorigenesis. Finally, inhibiting proteolysis by targeting LONP1 increases mitochondrial content in VHL-deficient cells and sensitizes therapy-resistant tumours to sorafenib treatment. Our results offer pharmacological avenues to sensitize therapy-resistant VHL tumours by focusing on the mitochondria.

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