Hypoxia Signaling and Circadian Disruption in and by Pheochromocytoma

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.

A multidisciplinary perspective on the complex interactions between sleep, circadian, and metabolic disruption in cancer patients

“…In this context, glycolysis-mediated acidification drives inhibition of the mammalian target of rapamycin complex 1 (mTORC1), which in turn suppresses the circadian clock in the cells [ 120 ]. As discussed previously, there is extensive crosstalk between hypoxia-inducible and circadian clock transcription factors within the cells [ 23 , 121 ] providing a further mechanism for suppression of circadian function in hypoxic tumor cells. Genetic disruption of the clock in the tumor cells may, however, also contribute to the Warburg effect.…”

Tumour Regression via Integrative Regulation of Neurological, Inflammatory, and Hypoxic Tumour Microenvironment

“…Melatonin (N-acetyl-5-methoxy-tryptamine), known as a biological clock regulator, has been implicated in the induction of apoptosis, cell cycle arrest, proliferation inhibition, and immune regulation (Vijayalaxmi et al, 2002). Defects in biological clock and activation of the sympathetic nerve are induced by various interactions between neurological factors and tumour microenvironment resulting in the progression of cancer (Tabebi et al, 2018;Verlande and Masri, 2019).…”

Role of Sphingosylphosphorylcholine in Tumor and Tumor Microenvironment

“…Melatonin (N-acetyl-5-methoxy-tryptamine), known as a biological clock regulator, is implicated in the induction of apoptosis, cell cycle arrest, proliferation inhibition, and immune regulation [153]. Defects in the biological clock and activation of the sympathetic nerve system are induced by various interactions between neurological factors and tumor microenvironment resulting in cancer progression [154,155].…”