Chronobiology of Cancers in the Liver and Gut

Abstract

Circadian rhythms dictate the timing of cellular and organismal physiology to maintain homeostasis. Within the liver and gut, circadian rhythms influence lipid and glucose homeostasis, xenobiotic metabolism, and nutrient absorption. Disruption of this orchestrated timing is known to negatively impact human health and contribute to disease progression, including carcinogenesis. Dysfunctional core clock timing has been identified in malignant growths and may be used as a molecular signature of disease progression. Likewise, the circadian clock and its downstream effectors also represent potential for novel therapeutic targets. Here, the role of circadian rhythms in the pathogenesis of cancers of the liver and gut will be reviewed, and chronotherapy and chronopharmacology will be explored as potential treatment options.

Keywords: cholangiocarcinoma; chronotherapy; circadian rhythms; colorectal cancer; hepatocellular carcinoma.

Figure 1

Mammalian circadian rhythms. Circadian rhythms are driven by a transcriptional-translational feedback loop. The core clock proteins CLOCK and BMAL1 heterodimerize and drive gene transcription of PER1/2 and CRY1/2. PER and CRY proteins feedback inhibit CLOCK/BMAL1 interactions, thus inhibiting PER/CRY translation. PER and CRY are phosphorylated by CK1, which leads to their ubiquitin-mediated degradation as well as completion of a 24 h cycle. BMAL1 is also regulated by accessory clock proteins; REV-ERBα inhibits BMAL1 while RORα induces BMAL1. Arrowhead indicates pathway activation, flathead indicates inhibition.

Figure 2

Circadian regulation of drug metabolism. The circadian clock directly or indirectly regulates all aspects of drug absorption, distribution, metabolism, and excretion. Absorptive drug transporters and excretory drug exporters in the intestine and other tissues are regulated by circadian rhythms, and the distribution of drugs is dependent upon rhythmic changes in cardiovascular function and plasma proteins. Drugs metabolized in the liver are subject to circadian regulation of cytochrome P450 enzymes (CYP enzymes) and the hepatobiliary transporters responsible for drug uptake into hepatocytes and secretion into bile. Finally, elimination and excretion of drugs are rhythmically controlled via changes in renal blood flow, tubular secretion rates, and urinary pH.