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. 2015 Dec;65(6):473-85.

Daytime Blue Light Enhances the Nighttime Circadian Melatonin Inhibition of Human Prostate Cancer Growth

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Free PMC article

Daytime Blue Light Enhances the Nighttime Circadian Melatonin Inhibition of Human Prostate Cancer Growth

Robert T Dauchy et al. Comp Med. .
Free PMC article

Abstract

Light controls pineal melatonin production and temporally coordinates circadian rhythms of metabolism and physiology in normal and neoplastic tissues. We previously showed that peak circulating nocturnal melatonin levels were 7-fold higher after daytime spectral transmittance of white light through blue-tinted (compared with clear) rodent cages. Here, we tested the hypothesis that daytime blue-light amplification of nocturnal melatonin enhances the inhibition of metabolism, signaling activity, and growth of prostate cancer xenografts. Compared with male nude rats housed in clear cages under a 12:12-h light:dark cycle, rats in blue-tinted cages (with increased transmittance of 462-484 nm and decreased red light greater than 640 nm) evinced over 6-fold higher peak plasma melatonin levels at middark phase (time, 2400), whereas midlight-phase levels (1200) were low (less than 3 pg/mL) in both groups. Circadian rhythms of arterial plasma levels of linoleic acid, glucose, lactic acid, pO2, pCO2, insulin, leptin, and corticosterone were disrupted in rats in blue cages as compared with the corresponding entrained rhythms in clear-caged rats. After implantation with tissue-isolated PC3 human prostate cancer xenografts, tumor latency-to-onset of growth and growth rates were markedly delayed, and tumor cAMP levels, uptake-metabolism of linoleic acid, aerobic glycolysis (Warburg effect), and growth signaling activities were reduced in rats in blue compared with clear cages. These data show that the amplification of nighttime melatonin levels by exposing nude rats to blue light during the daytime significantly reduces human prostate cancer metabolic, signaling, and proliferative activities.

Figures

Figure 1.
Figure 1.
Photoimage showing the standard polycarbonate translucent clear (left) and blue (right) rodent cages. Both cages had the same dimensions (19 in. × 10.5 in × 8.0 in; wall thickness, 0.1 in) and were autoclavable to 121 °C.
Figure 2.
Figure 2.
Spectral power distributions of the fluorescent lamp light as transmitted through the blue (experimental) and clear (control) cages.
Figure 3.
Figure 3.
Diurnal plasma melatonin levels (pg/mL; mean ± 1 SD) of male pigmented nude rats (n = 12 per group) maintained for 6 wk in standard polycarbonate, translucent, clear cages (control; solid red circles) or blue cages (experimental; solid blue squares) under 12:12-h photoperiods. Both groups were exposed similarly during the light phase (300 lx, 123 µW/cm2); during the 12-h dark phase (1800 to 0600; dark bars), rats had no exposure to light. Data are plotted twice to better demonstrate rhythmicity (panel A) and clarity of scale (panel B). Rhythmicity analysis (Table 3) revealed robust and highly significant (P < 0.0001) rhythmic patterns under control lighting conditions for both groups, with 9.6- (A) and 53.3- (B) fold increases in nighttime amplitude compared with daytime amplitudes, respectively, and a 5.55-fold increase (P < 0.001, Student t test) in amplitude at 2400 in rats in blue compared with clear cages. Concentrations with asterisks differ (P < 0.05) from concentrations without asterisks.
Figure 4.
Figure 4.
Diurnal changes in the blood plasma total fatty (TFA) and linoleic (LA) levels (µg/mL; mean ± 1 SD) of male pigmented nude rats (n = 12 per group) with unrestricted access to normal chow and maintained on either control (TFA, solid black circles; LA, solid red triangles) or experimental (TFA, solid blue squares; LA, solid inverted amber triangles) lighting conditions. Rats were exposed to dark-phase lighting conditions (see Methods) from 1800 to 0600 (dark bars). TFA values (mean ± 1 SD; n = 12 per group) are the sums of myristic, palmitic, palmitoleic, stearic, oleic, linoleic, and arachidonic acid concentrations collected at the various time points. Data are plotted twice to better demonstrate rhythmicity. Rhythmicity analysis (Table 3) revealed robust and highly significant (P < 0.0001) rhythmic patterns under control lighting conditions for both groups, with a greater than 6-fold increase in nighttime amplitude compared with daytime amplitude in both groups. Concentrations with asterisks differ (P < 0.05) from concentrations without asterisks.
Figure 5.
Figure 5.
Diurnal changes in arterial blood (A) glucose, (B) lactate, (C) pO2, and (D) pCO2 levels (mean ± 1 SD; n = 12 per group) of male nude rats maintained under either control (solid black circles) or experimental (solid blue triangles) lighting conditions. Rats were exposed to dark-phase lighting conditions from 1800 to 0600 (dark bars). Data are plotted twice to better visualize rhythmicity. Rhythmicity analysis (Table 3) revealed robust and highly significant (P < 0.0001) rhythmic patterns for both control (A) and experimental (B) groups but a significantly disrupted (P < 0.05) phase pattern only for rats in blue cages. *, Value differs significantly (P < 0.001, Student t test) between experimental and control conditions; concentrations with asterisks differ (P < 0.05) from concentrations without asterisks.
Figure 6.
Figure 6.
Diurnal changes in plasma (A) corticosterone, (B) insulin, and (C) leptin concentrations (mean ± 1 SD; n = 12 per group) in the arterial blood of rats maintained on either control (solid black circles) or experimental (solid blue squares) lighting conditions. Data are plotted twice to better demonstrate rhythmicity. Rats were exposed to dark-phase lighting conditions from 1800 to 0600 (dark bars). Rhythmicity analysis (Table 3) revealed robust and highly significant (P < 0.0001) rhythmic patterns under control conditions, significant (P < 0.05) but disrupted rhythmic patterns under experimental conditions for corticosterone, insulin, and leptin. *, Value differs significantly (P < 0.001) between experimental and control conditions; concentrations with asterisks are different (P < 0.05) than concentrations without asterisks.
Figure 7.
Figure 7.
Effects on tissue-isolated PC3 human prostate cancer xenografts growing in nude male rats after implantation (day 0) in rats housed in blue cages (solid blue triangles) compared with those in clear cages (solid red circles). Each point represents the mean (± 1 SD) estimated tumor weight mean (n = 12 per group). Tumor growth rates differed significantly (P < 0.001) between groups.
Figure 8.
Figure 8.
Western blot analysis for the expression of phosphorylated (upper panels) and total (lower panels) forms of AKT, NFκB, GSK3β, ERK 1/2, CREB, and PDK1 in the tumors of the control rats at 0800 (lane A) or of the blue-caged rats at 0800 (lane B), 1200 (lane C), or 2400 (lane D).

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