Roles of circadian clocks in cancer pathogenesis and treatment

Abstract

Circadian clocks are ubiquitous timing mechanisms that generate approximately 24-h rhythms in cellular and bodily functions across nearly all living species. These internal clock systems enable living organisms to anticipate and respond to daily changes in their environment in a timely manner, optimizing temporal physiology and behaviors. Dysregulation of circadian rhythms by genetic and environmental risk factors increases susceptibility to multiple diseases, particularly cancers. A growing number of studies have revealed dynamic crosstalk between circadian clocks and cancer pathways, providing mechanistic insights into the therapeutic utility of circadian rhythms in cancer treatment. This review will discuss the roles of circadian rhythms in cancer pathogenesis, highlighting the recent advances in chronotherapeutic approaches for improved cancer treatment.

Fig. 1. Circadian molecular clock mechanism.

This autoregulatory feedback loop cycles between the CLOCK/BMAL1 transcriptional activator complex and its repressors (PER/CRY, REV-ERBα) or activators (RORα/β) to constitute the molecular clock oscillator that drives the expression of multiple clock-controlled genes (CCGs), such as metabolic genes, signaling genes, and epigenetic regulators.

Fig. 2. Circadian clock systems.

The SCN central clock in the brain, primarily entrained by light, orchestrates circadian phases not only in non-SCN subordinate brain clocks via rhythmic release of neurotransmitters and neuropeptides but also in peripheral organ clocks via systemic hormonal secretion and neural innervations. Nonphotic external cues (e.g., temperature changes, food intake, exercise, and pathogens) can reset circadian rhythms in peripheral clock tissues, thereby influencing rhythmic output physiology and behaviors.

Fig. 3. Chronodisruptive factors and chronotherapeutic interventions in cancer pathogenesis and treatment.

Circadian clocks reciprocally interact with multiple pathways involved in cellular homeostasis and metabolism. Circadian rhythm disruptions caused by genetic, environmental, and pathological risk factors promote cancer onset and progression characterized by cancer hallmarks. Conversely, several types of chronotherapeutic interventions can enhance or restore circadian rhythms to reduce cancer pathogenesis and improve the response to anticancer treatment. MBL morning bright light, MEL melatonin, GCs glucocorticoids, CR caloric restriction, IF intermittent fasting.

Fig. 4. Divergent roles of circadian clock components in cancer.

Enhanced levels or activity of circadian clock components (e.g., CLOCK/BMAL1) inhibit tumor proliferation and growth by promoting the degradation of oncoproteins (e.g., cMYC, E2F, and TLK2), cell cycle arrest, apoptotic cell death, metabolic defects, and cytotoxic immunity in multiple cancers, as indicated. On the other hand, the core clock components may also exert tumor-suppressive functions in some cancer cell types (e.g., mesothelioma, leukemia stem cells, glioblastoma stem cells) by inhibiting tumor progression upon downregulation. E2F early 2 factor, TLK2 tousled like kinase 2.

Fig. 5. Circadian timing of cancer medicine.

The purpose of chronotherapy in anticancer medicine is to improve host tolerance and safety (a) or tumor cytotoxicity (b). a Chronotissue tolerance in anticancer therapy. The antiphasic peak and trough levels of dihydropyrimidine dehydrogenase (DPD), an elimination enzyme of 5-FU, and thymidine synthase (TS) in host tissues are associated with reduced toxicity with 5-FU treatment. Daily variation in the levels of glutathione (GSH), a potent antioxidant, is another host chronotolerance biomarker to consider when platinum-based anticancer drugs (e.g., oxaliplatin and cisplatin) are used. For example, doxorubicin is more effective and causes fewer side effects with morning treatment. b Chronotumor toxicity of antitumor agents. Daily rhythms in the tumor-specific cell cycle can be targeted by various cell cycle-specific anticancer drugs, including those that target the G1 phase (seliciclib), G–S phase transition (palbociclib), S phase (5-FU), and M phase (docetaxel). G; cell growth, S; DNA synthesis, M; mitosis. c Circadian regulation of the time-of-day specificity of antitumor drugs. Circadian clock function in tumors regulates cell cycle rhythms that mediate the dose-time-dependent cytotoxicity of antitumor drugs. Genetic ablation of BMAL1 (BMAL1 KO; dashed line) in tumors abolishes cell cycle rhythms and the time-of-day-specific drug sensitivity present in intact tumor cells (BMAL1 WT; solid line).