Effect of Daytime Blue-enriched LED Light on the Nighttime Circadian Melatonin Inhibition of Hepatoma 7288CTC Warburg Effect and Progression

Abstract

Liver cancer is the second leading cause of cancer death worldwide. Metabolic pathways within the liver and liver cancers are highly regulated by the central circadian clock in the suprachiasmatic nuclei (SCN). Daily light and dark cycles regulate the SCN-driven pineal production of the circadian anticancer hormone melatonin and temporally coordinate circadian rhythms of metabolism and physiology in mammals. In previous studies, we demonstrated that melatonin suppresses linoleic acid metabolism and the Warburg effect (aerobic glycolysis)in human breast cancer xenografts and that blue-enriched light (465-485 nm) from light-emitting diode lighting at daytime (bLAD) amplifies nighttime circadian melatonin levels in rats by 7-fold over cool white fluorescent (CWF) lighting. Here we tested the hypothesis that daytime exposure of tissue-isolated Morris hepatoma 7288CTC-bearing male rats to bLAD amplifies the nighttime melatonin signal to enhance the inhibition of tumor growth. Compared with rats housed under a 12:12-h light:dark cycle in CWF light, rats in bLAD light evinced a 7-fold higher peak plasma melatonin level at the mid-dark phase; in addition, high melatonin levels were prolonged until 4 h into the light phase. After implantation of tissue-isolated hepatoma 7288CTC xenografts, tumor growth rates were markedly delayed, and tumor cAMP levels, LA metabolism, the Warburg effect, and growth signaling activities were decreased in rats in bLAD compared with CWF daytime lighting. These data show that the increased nighttime circadian melatonin levels due to bLAD exposure decreases hepatoma metabolic, signaling, and proliferative activities beyond what occurs after normal melatonin signaling under CWF light.

Melatonin as an Antitumor Agent against Liver Cancer: An Updated Systematic Review

“…An in vitro and in vivo combined study, using 7288CTC HCC cells and 7288CTC tumor xenografts in situ, has shown that exposure to daytime blue-enriched LED light can reduce tumor progression by a mechanism associated with increase in the endogenous melatonin levels. This drives the inhibition of hepatoma metabolism through suppression of the Warburg effect (glucose uptake and lactate production) and impeding cyclic AMP (cAMP)-depending linoleic acid uptake [ 52 ].…”

Cancer and the Circadian Clock

“…Cancer-associated reprogramming of energy metabolism to predominantly utilize glycolytic activity, despite aerobic conditions (Warburg effect), is characterized with higher NADPH formation, decreased TCA cycle activity, and increased fatty acid synthesis (98), and recent studies established a relationship between this process and the circadian clock. For example, melatonin elevation due to light exposure changes leads to decreased growth of prostate and breast cancer xenografts due to disruption of the Warburg effect (99)(100)(101)(102)(103). In addition, alterations in the pentose phosphate pathway, which generates NADPH, is tightly controlled in a circadian manner (96).…”

Melatonin and circadian rhythms in liver diseases: Functional roles and potential therapies

“…During 12:12 light‐dark cycle, exposure to blue‐enriched light (increased transmittance of 462‐484 nm and decreased red light greater than 640 nm) at daytime using blue‐tinted cages increased plasma levels of melatonin at nighttime in rats . This blue light treatment followed by promotion of melatonin secretion at night inhibited tumor growth in xenograft rat models with Morris 7288CTC hepatoma although detailed mechanisms are undefined . Diethylnitrosamine (DEN) administration is utilized to induce HCC in rodents as an animal model of HCC .…”

“…82 This blue light treatment followed by promotion of melatonin secretion at night inhibited tumor growth in xenograft rat models with Morris 7288CTC hepatoma although detailed mechanisms are undefined. 83 Diethylnitrosamine (DEN) administration is utilized to induce HCC in rodents as an animal model of HCC. 84 A previous study administered melatonin (5 or 10 mg/kg per day for 10, 20, 30, or 40 weeks via i.p.…”