Abstract 222: Exposure to dim light at night disrupts the nocturnal melatonin signal in male nude rats bearing tissue-isolated castration-sensitive VCaP human prostate cancer: Impact on tumor circadian dynamics of the Warburg effect, lipid signaling and proliferation

Abstract

Abstract Over 248,000 men in the U.S. alone this year will be diagnosed with prostate cancer, and over 33,300 will die from the disease. The World Health Organization, in the case of breast cancer, has classified night-shift work involving light at night (LAN)-induced circadian disruption to be a probable carcinogen (Class 2A). Exposure to LAN suppresses nighttime pineal melatonin (MLT) production that influences normal and neoplastic tissue metabolism, physiology, and proliferation. Previously, we showed in rodent and human tumors in vivo that MLT inhibits linoleic acid (LA)-uptake and conversion to 13-hydroxyoctadecadienoic acid (13-HODE), a lipoxygenase product that enhances epidermal growth factor and insulin-like growth factor-I-induced mitogenesis. Recently, we developed a tissue-isolated, castration-sensitive VCaP human prostate cancer xenograft model to test the hypothesis that suppression of the nocturnal MLT signal due to exposure to dim LAN (dLAN) accelerates tumor LA-uptake and metabolism, aerobic glycolysis (Warburg Effect), and proliferative activity. Male nude rats (Crl:NIHFoxn1rnu; n=6/group) bearing castration-sensitive VCaP human prostate cancer xenografts were maintained on either a control L(300 lux)D(0 lux),12:12 or experimental LD,12:12dLAN (300 lux light phase followed by dLAN 0.2 lux dark phase intensity) light/dark cycle. Results revealed (Mean ± S.D.) plasma MLT levels in controls peaked in the mid-dark phase (183.4 ± 12.8 pg/mL) and were lowest (2.2 ± 0.4 pg/mL) in the mid-light phase, and low (< 10 pg/mL) throughout the 24-hr period in dLAN rats. Tumors in rats exposed to dLAN exhibited a significantly shorter latency to onset and a two-fold faster growth rate than controls. Harvested control group tumors revealed elevated cAMP levels, LA uptake, 13-HODE production, the Warburg effect, and [3H]thymidine incorporation into DNA, as well as elevated patterns of expression of signaling pathways phospho-ERK1/2, -AKT, -STAT3, -glycogen synthase kinase-3β (GSK3β), and -NF-κβ, and full-length androgen receptor and aldo-keto reductase (AKR1C3), during the light phase and markedly suppressed during the dark phase. In the dLAN group, these measures were markedly elevated throughout the 24-hr period. This is the first evidence in vivo, that dLAN-induced disruption of integrated circadian rhythms of signaling, metabolism, and proliferation results in accelerated growth of castration-sensitive human prostate cancer xenografts. Thus, lighting design strategies to minimize human exposure to LAN that preserve the integrity of the circadian MLT signal may offer a novel approach to suppress the growth progression of human castration-sensitive prostate cancer in our increasingly 24-hour society. Citation Format: Erin M. Dauchy, Robert T. Dauchy, Steven M. Hill, Yan Dong, Victoria P. Belancio, Shulin Xiang, George C. Brainard, John P. Hanifin, David E. Blask. Exposure to dim light at night disrupts the nocturnal melatonin signal in male nude rats bearing tissue-isolated castration-sensitive VCaP human prostate cancer: Impact on tumor circadian dynamics of the Warburg effect, lipid signaling and proliferation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 222.