Metabolism and Cancer: The Circadian Clock Connection

Saurabh Sahar; Paolo Sassone-Corsi

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Abstract and Introduction

Abstract

Circadian rhythms govern a remarkable variety of metabolic and physiological functions. Accumulating epidemiological and genetic evidence indicates that the disruption of circadian rhythms might be directly linked to cancer. Intriguingly, several molecular gears constituting the clock machinery have been found to establish functional interplays with regulators of the cell cycle, and alterations in clock function could lead to aberrant cellular proliferation. In addition, connections between the circadian clock and cellular metabolism have been identified that are regulated by chromatin remodelling. This suggests that abnormal metabolism in cancer could also be a consequence of a disrupted circadian clock. Therefore, a comprehensive understanding of the molecular links that connect the circadian clock to the cell cycle and metabolism could provide therapeutic benefit against certain human neoplasias.

Introduction

The process of tumorigenesis is intimately linked to the disruption of the balance that characterizes homeostasis.[1] Independent of the causal agents, it is now accepted that the aberration of specialized metabolic pathways may contribute to cell transformation. Cancer cells predominantly use glycolysis rather than mitochondrial oxidative phosphorylation for energy production, which is known as the Warburg effect.[2] Although the molecular gears that intersect metabolic control and the aberrant cellular proliferation that is characteristic of tumour cells are not fully deciphered,[3] several intriguing hints indicate that the cellular machinery that governs circadian physiology is likely to occupy a strategic signalling position.[4,5] This idea is particularly relevant as emerging evidence has revealed tight links between the molecular clock and the regulation of cellular metabolism.[6]

The Earth's rotation around its axis leads to day–night cycles, which affects the physiology of most living organisms. Circadian (from the Latin circa diem meaning 'about a day') clocks are intrinsic, time-tracking systems that enable organisms to anticipate environmental changes (such as food availability and predatory pressure) and allow them to adapt their behaviour and physiology to the appropriate time of day.[7] Rhythms that occur with a periodicity of 24 hours are considered circadian. Feeding behaviour, sleep–wake cycles, hormone levels and body temperature are just a few examples of physiological circadian rhythms, with light being the principal regulator or zeitgeber. The three integral parts of circadian clocks are an input pathway that includes detectors to receive environmental cues (or zeitgebers) and transmit them to the central oscillator, a central oscillator that keeps circadian time and generates rhythm, and output pathways through which the rhythms are manifested by the control of various metabolic, physiological and behavioural processes. The distinguishing characteristics of circadian clocks are that they are entrainable (that is, circadian clocks can be synchronized by external cues), self-sustained (oscillations can persist even in the absence of environmental cues) and temperature compensated (meaning that moderatevariations in ambient temperature do not affect the period of circadian oscillation).[8]

A major consequence of a modern lifestyle is the disruption of circadian rhythms. This leads to several pathological conditions, including sleep disturbances and depression. Importantly, accumulating evidence shows that the alteration of circadian rhythms might lead to increased susceptibility to cancer in humans. Epidemiological studies have revealed that the risk for breast cancer is significantly higher in industrialized societies, and that the risk increases as developing countries become more westernized.[9] Moreover, a moderate increase in the incidence of breast cancer is reported in women who work night shifts, and the incidence is higher among individuals who spend more hours per week and years working at night.[10,11] Exposure to light at night and the subsequent reduction in melatonin levels has been postulated to be a causal factor for this effect.[9] Importantly, although the correlation between lower melatonin levels and higher incidence of breast cancer was observed in one study,[12] another group failed to observe such a correlation.[13] However, from a clinical point of view, cancer prognosis is poorer in patients with an altered circadian rhythm than in patients with a normal rhythm.[14] In addition, chronotherapy (drug administration based on the time of the day (Box 1)) has been shown to improve the efficacy of some chemotherapeutic agents,[15,16] underscoring the importance of understanding circadian rhythmicity. In this Review, we discuss the molecular mechanisms whereby the circadian clock regulates the cell cycle, DNA damage responses, ageing and metabolism. Aberrant circadian rhythms could lead to defects in the regulation of these processes, which might result in tumorigenesis and tumour progression.

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