Dataset Information

Circadian Rhythm Disruption as a Contributor to Racial Disparities in Prostate Cancer.

ABSTRACT: In the United States, African American (AA) men have a 2.4 times higher mortality rate due to prostate cancer than White men. The multifactorial causes of the racial disparities in prostate cancer involve various social determinants of health, socioeconomic status, and access to healthcare. However, emerging evidence also suggests that circadian rhythm disruption (CRD) contributes to prostate cancer, and AA men may be more susceptible to developing CRDs. Circadian rhythms play a significant role in metabolism, hormone secretion, and sleep/wake cycles. Disruption in these circadian rhythms can be caused by airplane travel/jetlag, night shift work, exposure to light, and neighborhood noise levels, which can contribute to sleep disorders and chronic conditions such as obesity, diabetes, cardiovascular disease, and depression. The drivers of the racial disparities in CRD include night shift work, racial discrimination, elevated stress, and residing in poor neighborhoods characterized by high noise pollution. Given the increased vulnerability of AA men to CRDs, and the role that CRDs play in prostate cancer, elucidating the clock-related prostate cancer pathways and their behavior and environmental covariates may be critical to better understanding and reducing the racial disparities in prostate cancer.

SUBMITTER: Dasari SS

PROVIDER: S-EPMC9600368 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature

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Circadian Rhythm Disruption as a Contributor to Racial Disparities in Prostate Cancer.

Dasari Sonali S SS Archer Maddison M Mohamed Nihal E NE Tewari Ashutosh K AK Figueiro Mariana G MG Kyprianou Natasha N

Cancers 20221019 20

In the United States, African American (AA) men have a 2.4 times higher mortality rate due to prostate cancer than White men. The multifactorial causes of the racial disparities in prostate cancer involve various social determinants of health, socioeconomic status, and access to healthcare. However, emerging evidence also suggests that circadian rhythm disruption (CRD) contributes to prostate cancer, and AA men may be more susceptible to developing CRDs. Circadian rhythms play a significant role ...[more]

PMID: 36291899

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Project description:Crosstalk between cellular metabolism and circadian rhythms is a fundamental building block of multicellular life, and disruption of this reciprocal communication could be relevant to degenerative disease, including cancer. Here, we investigated whether maintenance of circadian rhythms depends upon specific metabolic pathways, particularly in the context of cancer. We found that in adult mouse fibroblasts, ATP levels were a major contributor to overall levels of a clock gene luciferase reporter, although not necessarily to the strength of circadian cycling. In contrast, we identified significant metabolic control of circadian function in an in vitro mouse model of pancreatic adenocarcinoma. Metabolic profiling of a library of congenic tumor cell clones revealed significant differences in levels of lactate, pyruvate, ATP, and other crucial metabolites that we used to identify candidate clones with which to generate circadian reporter lines. Despite the shared genetic background of the clones, we observed diverse circadian profiles among these lines that varied with their metabolic phenotype: the most hypometabolic line had the strongest circadian rhythms while the most hypermetabolic line had the weakest rhythms. Treatment of these tumor cell lines with bezafibrate, a peroxisome proliferator-activated receptor (PPAR) agonist shown to increase OxPhos, decreased the amplitude of circadian oscillation in a subset of tumor cell lines. Strikingly, treatment with the Complex I antagonist rotenone enhanced circadian rhythms only in the tumor cell line in which glycolysis was also low, thereby establishing a hypometabolic state. We further analyzed metabolic and circadian phenotypes across a panel of human patient-derived melanoma cell lines and observed a significant negative association between metabolic activity and circadian cycling strength. Together, these findings suggest that metabolic heterogeneity in cancer directly contributes to circadian function, and that high levels of glycolysis or OxPhos independently disrupt circadian rhythms in these cells.

Dataset Information

Circadian Rhythm Disruption as a Contributor to Racial Disparities in Prostate Cancer.

Publications

Circadian Rhythm Disruption as a Contributor to Racial Disparities in Prostate Cancer.

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