Mitochondrial Metabolism Shows Promise as Target for Cancer Therapy

Navdeep Chandel, PhD, the David W. Cugell, MD, Professor of Medicine in the Division of Pulmonary and Critical Care and of Biochemistry and Molecular Genetics, was the senior author of the studies published in the journals Nature and Cell Metabolism.

Northwestern Medicine investigators have discovered the growth of cancerous tumors requires the activation of a specific biochemical process within the mitochondria of tumor cells, according to findings published in Nature, showing potential as a new target for cancer therapy.

The cell’s mitochondria is responsible for generating chemical energy needed to power biochemical functions within the cell. Its inner membrane is embedded with a series of five enzyme complexes called the electron transport chain (ETC), which is responsible for generating energy production via adenosine triphosphate (ATP) to drive various processes and functions within the cell.

The ETC also necessary for the growth of tumors, and previous studies have found that inhibiting the ETC is an ideal target for cancer therapy. However, the reason why a functional ETC is essential for tumor growth has remained unknown, according to Navdeep Chandel, PhD, the David W. Cugell, MD, Professor of Medicine in the Division of Pulmonary and Critical Care, and senior author of the study.

Additionally, ETC function is responsible for providing metabolites linked to the tricarboxylic acid cycle (TCA) that provide the building blocks for cell proliferation.

By analyzing osteosarcoma tumor cells, lung adenocarcinoma cells and leukemia cells deficient in one such complex known as mitochondrial complex III, the investigators discovered that cells which lacked the complex were unable to grow tumors. This suggested that cellular metabolism linked to complex III function is essential to drive tumor growth.

Ultimately, complex III’s ability to drive the TCA cycle but not ATP production was necessary for tumor growth, according to Chandel.

“In a normal cell, the mitochondria use oxygen to make ATP, but we show that’s not the case in tumor cells. They’re using that oxygen to drive the TCA cycle, which is linked to cell respiration, to generate metabolites for cancer growth,” said Chandel, who is also a professor of Biochemistry and Molecular Genetics and a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.

Inmaculada Martínez-Reyes, a postdoctoral fellow in the Chandel laboratory, was the first author of the study. Scott Budinger, MD, the Ernest S. Bazley Professor of Airway Diseases, chief of Pulmonary and Critical Care in the Department of Medicine, and a member of the Lurie Cancer Center, was a co-author.

Inhibiting Mitochondrial Metabolism

In a separate paper published in Cell Metabolism, Chandel and colleagues discussed the rationale behind using anti-cancer agents to inhibit mitochondrial metabolism as a new cancer therapeutic treatment, specifically using the drug metformin, which is primarily prescribed to patients with type 2 diabetes to control blood glucose levels.

Metformin has also been shown in previous studies to reduce cancer incidence. However, not all cancer cell lines fully respond to the drug, with some showing sensitivity to the drug but ultimately being resistant to therapy, according to Chandel.

Using CRISPR based genetic screening technology, the investigators led by Marie Werner, PhD, a postdoctoral fellow in the Chandel laboratory, analyzed a cancer cell line very sensitive to metformin to determine which gene, when missing, made the tumor cells resistant to treatment. The team found that loss of the gene SLC22A3 results in the failed transport of metformin into tumor cells.

“When doing a clinical trial, you should look at that transporter expression within the tumor. If it’s positive, give people metformin,” Chandel said.

According to Chandel, the next step will be to determine how the mitochondria controls metastasis, as well as tumor cells’ resistance to therapeutic interventions such as radiation, chemotherapy and immunotherapy.

Karthik Vasan, a third year graduate student in the Medical Scientist Training Program (MSTP), was the first author of the paper.

Both works were supported by the National Institutes of Health (NIH) grant 5R35CA197532.