Clock at the core of cancer development

Abstract

Simple Summary: The earth’s rotation produces a daily 24 h cycle of day and night. Many biological functions, such as sleep-wake cycle, feeding/fasting cycle, blood hormone levels and body temperature rhythms occur over a 24 h period. These daily fluctuations are controlled by an internal system known as the circadian clock (Latin circa-“around”-and diem-“day”). This clock coordinates the periodic changes in diverse physiological and behavioral activities and helps adapt to the periodic environment for the benefit of survival and reproduction of organisms. Nearly all organisms, from single-cell to mammals, including humans, possess a self-sustained circadian clock. Disturbances in the functioning of this internal circadian clock can alter the balance in biological functions and compromise organism fitness. In humans, clock disruption is associated with diseases such as diabetes, cardiovascular diseases and cancer. Thus, studying the interplay between the circadian clock and physiology is important in the prevention and management of fatal diseases such as cancer. To synchronize various biological processes with the day and night cycle, most organisms have developed circadian clocks. This evolutionarily conserved system is important in the temporal regulation of behavior, physiology and metabolism. Multiple pathological changes associated with circadian disruption support the importance of the clocks in mammals. Emerging links have revealed interplay between circadian clocks and signaling networks in cancer. Understanding the cross-talk between the circadian clock and tumorigenesis is imperative for its prevention, management and development of effective treatment options. In this review, we summarize the role of the circadian clock in regulation of one important metabolic pathway, insulin/IGF1/PI3K/mTOR signaling, and how dysregulation of this metabolic pathway could lead to uncontrolled cancer cell proliferation and growth. Targeting the circadian clock and rhythms either with recently discovered pharmaceutical agents or through environmental cues is a new direction in cancer chronotherapy. Combining the circadian approach with traditional methods, such as radiation, chemotherapy or the recently developed, immunotherapy, may improve tumor response, while simultaneously minimizing the adverse effects commonly associated with cancer therapies.