When lung cells are out of breath

RASSF1A and HIF-1alpha stimulate Warburg effect in cancer and pulmonary hypertension

If cells do not have enough oxygen availability, they convert their metabolism from efficient cellular respiration to far less efficient glycolysis. In tumor cells, glycolysis can occur even when sufficient oxygen is available. Scientists at the Max-Planck-Institute for Heart and Lung Research in Bad Nauheim have now discovered a molecular mechanism underlying this so-called Warburg effect: The protein RASSF1A is the center of a feed forward loop that helps cells respond to oxygen deficiency. The newly identified mechanism should serve as the basis for the development of innovative therapeutic approaches.

Scheme of self-boosting control loop.In case cells have little oxygen available (blue), they convert their cell metabolism. In the center is the protein RASSF1A, which is initially stabilized and thus can be active for a longer time (middle). This increases of HIF-1alpha activity. As a late reaction, it causes in turn more RASSF1A to be produced (right) - a self-reinforcing loop.

Almost a hundred years ago, biochemist Otto Warburg discovered a peculiarity in the metabolism of cancer cells: while healthy cells burn sugar to generate energy and consume oxygen, tumor cells gain their energy through the fermentation of glucose. This particularly happens even if sufficient oxygen is available. In contrast, healthy cells use this inefficient way of generating energy only when they do not have sufficient oxygen supply. A well-known example for this is the muscle metabolism: limited oxygen supply during strenuous exercise switch the muscle cells to produce lactate from glucose.

Until now, it was largely unclear why the "Warburg Effect", named after its discoverer, occurs in tumor cells. Scientists at the Max-Planck-Institute for Heart and Lung Research have now decrypted a feed-forward loop driving the Warburg effect. In addition, the feed-forward loop could also play an important role in hypoxia (low oxygen)-driven lung diseases.

Hypoxia activates transcription factor

"It has been known for some time that, in the case of hypoxia, a transcription factor called HIF-1alpha is activated in the affected cells. This regulates the response to the low oxygen levels, for example by adapting the cell metabolism, as cells divide or blood vessels begin to grow,” explains Swati Dabral, a scientist in the research group of Soni Pullamsetti and first author of the study. "We were now able to show that a protein called RASSF1A enhances the activity of HIF-1alpha," Dabral continued. At the same time, HIF-1alpha, together with other factors, activates the RASSF1A in the event of an oxygen deficiency. It is a self-reinforcing control loop.

The Max Planck researchers showed this process is active not only in tumor cells but also in healthy cells, that are exposed to hypoxia. "In response, the cells first stabilized existing RASSF1A molecules, followed by formation of additional RASSF1A molecules,” said Soni Pullamsetti, head of the research group. To prove the interaction with HIF-1alpha, the Max Planck researchers switched off RASSF1A by genetic engineering in the cells or, conversely, caused a strong increase in the production of the protein. "Loss of RASSF1A results in the loss of HIF-1alpha activity. On the other hand, overexpression of RASSF1A significantly increased the amount of HIF-1alpha, implying a RASSF1A-HIF-1α feedforward loop,” said Pullamsetti.

Important role in pulmonary hypertension

This loop plays an important role in various forms of pulmonary hypertension. Pulmonary hypertension is characterized by uncontrolled division of cells in the blood vessel walls. As a result, the vessel walls become increasingly thick. This, in turn, increases the blood pressure in the pulmonary arteries, which in the course of time damages the heart.

is characterized, among other things, by the fact that muscle cells in the wall of pulmonary arteries have an abnormal cell division and thereby greatly expand the vessel wall. In the laboratory, the Bad Nauheim researchers were able to prove the existence of RASSF1A-HIF-1α feedforward loop in pulmonary arterial smooth muscle cells isolated from pulmonary hypertensive, lungs where RASSF1A was shown to be responsible for both increased cell division and energy metabolism.

Werner Seeger, Director at the Max-Planck-Institute in Bad Nauheim and Director of the Medical Clinic II (Giessen) at the University Hospital Giessen and Marburg, therefore found it surprising to see a co-localization of RASSF1A and HIF-1alpha in samples of pulmonary hypertension patients: “Various forms of pulmonary hypertension are associated with hypoxia in the lung tissue. In our studies, we found increased levels of RASSF1A mRNA and protein in samples from pulmonary hypertensive patients. As this was associated with increased HIF-1alpha activity, the patient specimens confirmed our laboratory data,” said Seeger. Furthermore, the research team was also able to show that RASSF1A is influencing the cell metabolism of certain lung cancer cells and their proliferation activity in subgroups of lung cancer patients.

"Our study demonstrates the importance of RASSF1A on HIF-1alpha activity and the resulting changes in the regulation of certain genes, the adaptation of cell metabolism, and cell proliferation," said Pullamsetti. The Max Planck researchers hope to find new approaches in developing therapies for pulmonary hypertension or lung cancer - diseases that are related to the occurrence of hypoxia in the tissue.

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