Impact of Circadian Rhythms on the Development and Clinical Management of Genitourinary Cancers

Abstract

The circadian system is an innate clock mechanism that governs biological processes on a near 24-hour cycle. Circadian rhythm disruption (i.e., misalignment of circadian rhythms), which results from the lack of synchrony between the master circadian clock located in the suprachiasmatic nuclei (SCN) and the environment (i.e., exposure to day light) or the master clock and the peripheral clocks, has been associated with increased risk of and unfavorable cancer outcomes. Growing evidence supports the link between circadian disruption and increased prevalence and mortality of genitourinary cancers (GU) including prostate, bladder, and renal cancer. The circadian system also plays an essential role on the timely implementation of chronopharmacological treatments, such as melatonin and chronotherapy, to reduce tumor progression, improve therapeutic response and reduce negative therapy side effects. The potential benefits of the manipulating circadian rhythms in the clinical setting of GU cancer detection and treatment remain to be exploited. In this review, we discuss the current evidence on the influence of circadian rhythms on (disease) cancer development and hope to elucidate the unmet clinical need of defining the extensive involvement of the circadian system in predicting risk for GU cancer development and alleviating the burden of implementing anti-cancer therapies.

Keywords: CLOCK proteins; bladder cancer; chronotherapy; circadian rhythm; genitourinary cancers; kidney cancer; melatonin; prostate cancer.

Figure 1

Genetic Outcomes of the Circadian Clock Proteins and Clinical Management Techniques. Circadian clock transcription-translation feedback loop (TTFL) is controlled by two activator proteins Brain and Muscle ARNT-Like 1 (BMAL1) and Circadian Locomotor Output Cycles Kaput (CLOCK), and two repressor proteins, Period (PER) and Cryptochrome (CRY). BMAL1 and CLOCK heterodimerize and bind to the E-box motif to activate the transcription of CRY (1-2), PER (1-3), clock-controlled genes (CCGs), RORα, REV-ERBα. CRY and PER establish the primary negative feedback loop by inhibiting the BMAL1 and CLOCK heterodimer. In the secondary feedback loop, RORα activates, and REV-ERBα inhibits the transcription of BMAL1. Circadian clock proteins mediate several cancer pathways such as cell cycle regulation, DNA damage repair, apoptosis, and hormonal changes. Melatonin binds to the MT1 and MT2 receptors and targets inflammation and survival pathways by preventing the translocation of NF-κB to the nucleus. Melatonin interferes with EMT and metastasis by downregulating β-catenin through activation of GSK-3β and inhibiting the expression of matrix metalloproteinases-9 and -13. The inhibition of endothelin-1 (ET-1) by melatonin leads to reduced activity of angiogenic factors HIF-1α and VEGFA.