Circadian Oscillations Persist in Cervical and Esophageal Cancer Cells Displaying Decreased Expression of Tumor-Suppressing Circadian Clock Genes.

There is accumulating evidence for a link between circadian clock disruption and cancer progression. In this study, the circadian clock was investigated in cervical and esophageal cancers, to determine whether it is disrupted in these cancer types. Oncomine datamining revealed downregulation of multiple members of the circadian clock gene family in cancer patient tissue compared with matched normal epithelium. Real-time RT-PCR analysis confirmed significant downregulation of CLOCK, PER1, PER2, PER3, CRY1, CRY2, REV-ERBα, and RORα in esophageal tumor tissue. In cell line models, expression of several circadian clock genes was significantly decreased in transformed and cancer cells compared with noncancer controls, and protein levels were dysregulated. These effects were mediated, at least in part, by methylation, where CLOCK, CRY1, and RORα gene promoter regions were found to be methylated in cancer cells. Overexpression of CLOCK and PER2 in cancer cell lines inhibited cell proliferation and activation of RORα and REV-ERBα using agonists resulted in cancer cell death, while having a lesser effect on normal epithelial cells. Despite dysregulated circadian clock gene expression, cervical and esophageal cancer cells maintain functional circadian oscillations after Dexamethasone synchronization, as revealed using real-time bioluminescence imaging, suggesting that their circadian clock mechanisms are intact. IMPLICATIONS: This study is a first to describe dysregulated, yet oscillating, circadian clock gene expression in cervical and esophageal cancer cells, and knowledge of circadian clock functioning in these cancer types has the potential to inform chronotherapy approaches, where the timing of administration of chemotherapy is optimized on the basis of the circadian clock.

The tumour suppressing role of the circadian clock.

The circadian clock and the ~24 h rhythms it generates are essential in maintaining regular tissue functioning. At the molecular level, the circadian clock comprises a core set of rhythmically expressed genes and gene products that are able to drive rhythmic expression of other genes to generate overt circadian rhythms. It has recently come to light that perturbations of circadian rhythms contribute to the development of pathological states such as cancer, and altered expression and/or regulation of circadian clock genes has been identified in multiple tumour types. This review summarises the important role the circadian system plays in regulating cellular processes, including the cell cycle, apoptosis, DNA repair, the epithelial-to-mesenchymal transition, metabolism and immunity and how its dysregulation has widespread implications and could be a critical player in the development of cancer. Understanding its role in cancer development is important for the field chronotherapy, where the timing of chemotherapy administration is optimised based on differences in circadian clock functioning in normal and cancer cells. This has been found to influence the patient response, minimising the side effects commonly associated with chemotherapy. © 2019 IUBMB Life, 2019.

Photolon, a chlorin e6 derivative, triggers ROS production and light-dependent cell death via necrosis.

Photolon is a photosensitiser with demonstrated potential as an anti-tumour agent. In this study, an in vitro investigation was performed to determine the mechanism of Photolon-induced cell death. Cell killing was observed in a light-dependent manner and light-activated Photolon resulted in a significant production of reactive oxygen species (ROS), which could be blocked by type I ROS scavengers. Inhibition of ROS production using Trolox prevented Photolon-induced cell death. Light-activated Photolon caused no increase in caspase-3/7 activity, but a rapid increase in lactate dehydrogenase (LDH) release suggesting a loss of membrane integrity and subsequent cell death by necrosis. We conclude that the mechanism of Photolon-induced cell death involves the induction of ROS via a type I mechanism, which is ultimately responsible for cell killing by necrosis.