title: WOMEN IN CANCER THEMATIC REVIEW: Circadian rhythmicity and the influence of 'clock' genes on prostate cancer.
abstract: The androgen receptor (AR) plays a key role in the development and progression of prostate cancer (CaP). Since the mid-1990s, reports in the literature pointed out higher incidences of CaP in some select groups, such as airline pilots and night shift workers in comparison with those working regular hours. The common finding in these 'high-risk' groups was that they all experienced a deregulation of the body's internal circadian rhythm. Here, we discuss how the circadian rhythm affects androgen levels and modulates CaP development and progression. Circadian rhythmicity of androgen production is lost in CaP patients, with the clock genes Per1 and Per2 decreasing, and Bmal1 increasing, in these individuals. Periodic expression of the clock genes was restored upon administration of the neurohormone melatonin, thereby suppressing CaP progression. Activation of the melatonin receptors and the AR antagonized each other, and therefore the tumour-suppressive effects of melatonin and the clock genes were most clearly observed in the absence of androgens, that is, in conjunction with androgen deprivation therapy (ADT). In addition, a large-scale study found that high-dose radiation was more effective in CaP patients when it was delivered before 17:00 h, compared with those delivered after 17:00 h, suggesting that the therapy was more effective when delivered in synchrony with the patient's circadian clock. As CaP patients are shown to become easily resistant to new therapies, perhaps circadian delivery of these therapeutic agents or delivery in conjunction with melatonin and its novel analogs should be tested to see if they prevent this resistance.
authors.affiliation: VA Northern California Health Care SystemMather, California, USA.|Department of UrologyUniversity of California at Davis, Sacramento, California, USA.
authors.forename: Zsofia
authors.initials: Z
authors.lastname: Kiss
authors.affiliation: VA Northern California Health Care SystemMather, California, USA paghosh@ucdavis.edu.|Department of UrologyUniversity of California at Davis, Sacramento, California, USA.|Department of Biochemistry and Molecular MedicineUniversity of California at Davis, Sacramento, California, USA.
authors.forename: Paramita M
authors.initials: PM
authors.lastname: Ghosh
mesh_terms: D000818:Animals; D056926:CLOCK Proteins / Q000235:genetics*; D057906:Circadian Clocks / Q000235:genetics*; D002940:Circadian Rhythm / Q000502:physiology*; D005260:Female; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology
chemical_list: D056926:CLOCK Proteins
keywords: androgen receptor; bmal1; circadian clock; melatonin; per1