‘Achilles Heel’ in Metabolic Pathway Could Lead to New Lung Cancer Treatments, According to Study

‘Achilles Heel’ in Metabolic Pathway Could Lead to New Lung Cancer Treatments, According to Study

shutterstock_202096720A novel study on lung cancer, entitled “Inhibition of Cancer Cell Proliferation by PPARγ Is Mediated by a Metabolic Switch that Increases Reactive Oxygen Species Levels” published in the Cell Metabolism journal, identified PPARγ as the “Achilles heel” in a metabolic pathway crucial to inhibit the growth of lung cancer cells.

Dr. Kittler and his team, from the Eugene McDermott Center for Human Growth and Development, The University of Texas Southwestern Medical Center, Dallas, identified that peroxisome proliferation-activated receptor gamma (PPARγ), a transcriptional master regulator of glucose and lipid metabolism activation, triggers changes in the metabolism of glucose and lipids, inducing an increase in the levels of reactive oxygen species (ROS).

Oxidative stress is characterized by high levels of ROS, which are potent reactive oxygen-containing molecules that can damage cells, ultimately inhibiting the division of cancer cells. Importantly, the authors showed that by activating PPARγ with antidiabetic drugs, such as thiazolidinediones, in lung cancer cells it could stop them from dividing.

“We found that activation of PPARγ causes a major metabolic change in cancer cells that impairs their ability to handle oxidative stress,” Dr. Ralf Kittler, Assistant Professor in the Eugene McDermott Center for Human Growth and Development, the Department of Pharmacology, the Harold C. Simmons Cancer Center, and the Cecil H. and Ida Green Center for Reproductive Biology Sciences at UT Southwestern, said in a University press release.kittler

“The increased oxidative stress ultimately inhibits the growth of the tumor. We found that activation of PPARγ killed both cancer cells grown in a dish and tumors in mice, in which we observed near complete tumor growth inhibition,” Dr. Kittler added in the press release.

“The abnormal metabolism in cancer cells frequently causes increased oxidative stress, and any further increase can ‘push’ cancer cells over  the cliff. This is an important finding because the drugs that activate PPARγ include FDA-approved antidiabetic drugs that are relatively well tolerated compared to chemotherapy. Knowing their mechanism of action provides us with clues for selecting tumors that may be responsive to this treatment, for combining these drugs with anti-cancer drugs to make therapy more effective, and for developing markers to measure the response of tumors to these drugs in patients”, Dr. Kittler concluded.

Overall, this study suggests that targeting PPARγ could be a potential new therapeutic approach for lung cancer and also for other cancers. Notably, the authors demonstrated that activating PPARγ caused similar molecular changes in breast cancer cells.

“Of course, further study will be required to determine the therapeutic effectiveness of PPARγ-activating drugs for lung cancer treatment,” concluded Dr. Kittler.

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