Abstract
Disruption of the daily (i.e., circadian) rhythms of cell metabolism, proliferation and blood perfusion is a hallmark of many cancer types, perhaps most clearly exemplified by the rare but detrimental pheochromocytomas. These tumors arise from genetic disruption of genes critical for hypoxia signaling, such as von Hippel-Lindau and hypoxia-inducible factor-2 or cellular metabolism, such as succinate dehydrogenase, which in turn impacts on the cellular circadian clock function by interfering with the Bmal1 and/or Clock transcription factors. While pheochromocytomas are often non-malignant, the resulting changes in cellular physiology are coupled to de-regulated production of catecholamines, which in turn disrupt circadian blood pressure variation and therefore circadian entrainment of other tissues. In this review we thoroughly discuss the molecular and physiological interplay between hypoxia signaling and the circadian clock in pheochromocytoma, and how this underlies endocrine disruption leading to loss of circadian blood pressure variation in the affected patients. We furthermore discuss potential avenues for targeting these tumor-specific pathophysiological mechanisms therapeutically in the future.
Highlights
Cancer is a growing health threat exhibiting relentlessly increasing incidence due to changes in the pro-tumorigenic environmental stressors of our modern lifestyle as well as improved longevity, screening programs and diagnostic capabilities
In tumors caused by transmembrane protein 127 (TMEM127) and MYCassociated factor X (MAX) mutations, mTORC activation could increase hypoxia-inducible factor (HIF)-1/2α levels [35]: Mutations in TMEM127 gene lead to enhancement of mTORC signaling in a Ras- and PI3K/AKT-independent manner[36]
The disruption of circadian signaling by hypoxia was recently found to depend on lactic-acid mediated acidification, via disruption of mTORC1 signaling, possibly pin-pointing the molecular intersection between these two pathways and suggesting that their intimate cross-talk can be uncoupled by interfering with lactic acid metabolism and mTOR/mTORC1 activity [60]
Summary
Edited by: Josefa Leon, Fundación para la Investigación Biosanitaria de Andalucía Oriental (FIBAO), Spain. Disruption of the daily (i.e., circadian) rhythms of cell metabolism, proliferation and blood perfusion is a hallmark of many cancer types, perhaps most clearly exemplified by the rare but detrimental pheochromocytomas. These tumors arise from genetic disruption of genes critical for hypoxia signaling, such as von Hippel-Lindau and hypoxia-inducible factor-2 or cellular metabolism, such as succinate dehydrogenase, which in turn impacts on the cellular circadian clock function by interfering with the Bmal and/or Clock transcription factors. In this review we thoroughly discuss the molecular and physiological interplay between hypoxia signaling and the circadian clock in pheochromocytoma, and how this underlies endocrine disruption leading to loss of circadian blood pressure variation in the affected patients.
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