Interplay between Circadian Clock and Cancer: New Frontiers for Cancer Treatment

Abstract

Circadian clocks constitute the evolutionary molecular machinery that dictates the temporal regulation of physiology to maintain homeostasis. Disruption of the circadian rhythm plays a key role in tumorigenesis and facilitates the establishment of cancer hallmarks. Conversely, oncogenic processes directly weaken circadian rhythms. Pharmacological modulation of core clock genes is a new approach in cancer therapy. The integration of circadian biology into cancer research offers new options for making cancer treatment more effective, encompassing the prevention, diagnosis, and treatment of this devastating disease. This review highlights the role of the circadian clock in tumorigenesis and cancer hallmarks, and discusses how pharmacological modulation of circadian clock genes can lead to new therapeutic options.

Keywords: cancer hallmarks; cancer therapy; circadian clock; circadian rhythms; tumorigenesis.

FIGURE 1.. Circadian clock: molecular mechanisms, natural ligands and, chemical tools.

The circadian clock machinery generates everyday circadian rhythms. The core clock mechanism presents activators and repressors and consists of two main loops. Several regulatory layers (transcriptional, post-translational, cytoplasm-nuclear translocation) are in play to ensure rhythmicity. Transcriptional activators BMAL1 and CLOCK/NPAS2 (NPAS2 substitutes for CLOCK in the forebrain) bind to DNA element E-box motif and trigger the expression of the repressors Period (PER1, PER2, PER3), Cryptochrome (CRY1 and CRY2). Upon accumulation PERs and CRYs interact, they are phosphorylated by Casein Kinase 1δ/ε and translocate to the nucleus where they block the transcriptional activity of BMAL1 and CLOCK/NPAS2 thus inhibiting their own transcription. Post-translational mechanisms driven by AMPK and FBXL3 will lead CRYs to degradation in the nucleus; cytoplasmic degradation of CRYs is instead regulated by CK1δ/ε and FBXL21. Several chemical tools have been developed to modulate CRYs and CK1δ/ε as displayed. PERs are degraded in the cytoplasm upon phosphorylation by CK1δ/ε and β-TRCP. In an additional loop BMAL1 and CLOCK/NPAS2 activate the transcription of REV-ERBα/β and RORα/β/γ proteins. These are respectively transcriptional repressors and activators that further ensure rhythmicity of BMAL expression. Both REV-ERBα/β and RORα/β/γ are nuclear hormone receptors that are modulated by natural ligands (in bold in the figure). REV-ERBα/β and RORα/β/γ are rapidly becoming a target of interest for pharmacology and several small molecules (in italic in the figure) have been developed in the recent years to modulate their activity.

FIGURE 2.. Circadian clock genes expression in cancer patients and their association with survival outcome.

a) Altered circadian clock genes expression in various cancer types compared to the normal tissues. Green represents cancers with downregulated circadian clock genes; red, upregulated. b) Table indicating the survival outcome associated with core clock gene (CCG) expression.

FIGURE 3, Key Figure.. Disruption of circadian rhythms during tumorigenesis and impact on cancer hallmarks.

Normal cells and tissues display circadian oscillations. A large body of evidence has connected circadian clock genes to several important regulatory nodes for cellular transformation. Given the pleiotropic role of the circadian clock in physiology it is not surprising that several cancer hallmarks are under circadian clock control. During cancer initiation circadian rhythms are disrupted by oncogenes; this suggests that loosening of the circadian clock function may facilitate the instauration of cancer hallmarks and play a fundamental role in tumorigenesis. Adapted from “Hallmarks of Cancer: The Next Generation,” 2011 Cell.

FIGURE 4.. Circadian clock interplay with cancer metabolic nodes.

Aerobic glycolytic switch is observed in many tumor types. Intriguingly circadian clock may control glycolysis in cancer cells through multiple steps. Several players sustaining aerobic glycolysis in cancer such as the PI3K/AKT cascade, GLUT transporters, LDHA, Myc and HIF are modulated by circadian rhythms. The extent of the interplay occurring between CLOCK, BMAL, MYC and HIF is not currently characterized and may unveil important connections affecting both glycolysis and glutaminolysis. Similarly, the tight interactions existing between glucose/lipid metabolism and clock genes have been only barely investigated for their relevance in cancer. Environmental changes associated with the cancerous state also affect the circadian clock. Hypoxia results in an acid microenvironment which block mTOR activity. mTOR has been recently suggested to play an important role in the translation of several core clock genes.

FIGURE 5.. Role of the circadian clock in the tumor-immune interactions and immunotherapy.

The circadian clock imposes rhythms in key components of the immune system and maintain homeostasis in inflammatory processes. Disruption of circadian rhythms affects multiple immune system functions and leads to chronic inflammation. These alterations foster tumor initiation, progression and metastasis. Intriguingly, the crosstalk occurring between the circadian clock and the immune system can be exploited for the generation of innovative immunotherapy approaches. Indeed, the RORγ agonist Lyc-55716 is currently tested in clinical trials as monotherapy and in combination with anti PD-1 in patients with advanced solid tumors. Interestingly, pharmacological activation of RORγ has a dual effect: lead to the activation of Th17 cells and attenuate immunosuppression. A similar effect could be achieved by activation of REV-ERBs