Impairment in mitochondrial oxidative phosphorylation alters clock gene expression
Date
2020-10-21
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Abstract
Epidemiological studies provide evidence that workers who perform chronic night shift work are
at significantly higher risk of a number of severe disease states including cancer. The perturbed
activity/rest and feeding/fasting cycles, which occurs in persons performing shift work or who
are subjected to jet lag, disrupt our normal 24- hour internal clock or circadian rhythm. The
molecular mechanisms that link chronic circadian disruption to disease are not well understood.
Since light exposure at night is known to decrease melatonin levels, some researchers have
hypothesized that a reduction in the nocturnal levels of this pineal hormone predisposes
individuals to disease. Animals that displayed atypical behaviours in their daily cycles, led to the
identification of eight-key clock or circadian genes that are differentially expressed during the
day and which determine normal internal timing. The expression of these genes was abnormal in
a large number of human tumors including breast cancer. In this study, a temperature shift
model was characterized and used as a means to synchronize the expression of these clock genes
in a human breast cancer cell line. The model was compared to another cell synchronization
protocol which utilizes serum shock and which showed differences in gene expression and cell
cycle regulation between the two protocols. The temperature shift model was then used to study
the impact of melatonin on clock gene expression and on the production of reactive oxygen
species (ROS) in cells exposed to chemotherapeutic drugs. Melatonin influenced the cell cycle
but did not cause significant differences in clock gene expression. Chemotherapeutic drugs
differed in their effects on the production of intracellular ROS. A mitochondrial deficient (Rhø)
cell line which exhibited impaired oxidative phosphorylation, was developed from MCF-7 cells.
The profile of clock gene expression in Rhø cells that were also subjected to the temperature shift
protocol was different than that of the parental MCF-7 line. This suggests that impairment of
mitochondrial function disrupts clock gene expression and may be a link to the oncogenic
transformation of cells.
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Keywords
Circadian disruption, Clock gene expression, Circadian cycle, Melatonin, Reactive Oxygen Species, Breast Cancer, Mitochondria, Oxidative Phosphorylation, Rhø cell