Light Exposure at Night Disrupts Host/Cancer Circadian Regulatory Dynamics: Impact on the Warburg Effect, Lipid Signaling and Tumor Growth Prevention

Abstract

The central circadian clock within the suprachiasmatic nucleus (SCN) plays an important role in temporally organizing and coordinating many of the processes governing cancer cell proliferation and tumor growth in synchrony with the daily light/dark cycle which may contribute to endogenous cancer prevention. Bioenergetic substrates and molecular intermediates required for building tumor biomass each day are derived from both aerobic glycolysis (Warburg effect) and lipid metabolism. Using tissue-isolated human breast cancer xenografts grown in nude rats, we determined that circulating systemic factors in the host and the Warburg effect, linoleic acid uptake/metabolism and growth signaling activities in the tumor are dynamically regulated, coordinated and integrated within circadian time structure over a 24-hour light/dark cycle by SCN-driven nocturnal pineal production of the anticancer hormone melatonin. Dim light at night (LAN)-induced melatonin suppression disrupts this circadian-regulated host/cancer balance among several important cancer preventative signaling mechanisms, leading to hyperglycemia and hyperinsulinemia in the host and runaway aerobic glycolysis, lipid signaling and proliferative activity in the tumor.

Melatonin: an inhibitor of breast cancer

“…Work by Santoro et al (2013) demonstrated that blockade of MT 1 /MT 2 receptors in MCF-7 cells impairs p53-mediated prevention of DNA damage. Other mechanisms associated with the anti-proliferative actions of melatonin include cell cycle with arrest of breast tumor cells in the G1 phase of the cell cycle (Cos et al 1991), repression of estrogen synthesis in the gonads (Blask et al 2011) or the tumor by repression of aromatase (Martínez-Campa et al 2009), and finally by suppression of tumor metabolism (Warburg effect) via repression of tumor uptake of free fatty acids, particularly linoleic acid and its conversion to 13-hydroxyoctadecadienoic acid (13-HODE) (Reiter 1991; Blask et al 2014). …”

“…For example, in human breast cancer xenografts grown in athymic female nude rats, greatly elevated tumor uptake of LA and metabolism to 13-HODE and aerobic glycolysis during the daytime are involved in promoting a corresponding increase in cell proliferative/survival activities in tumors, whereas during the nighttime, these processes become quiescent as shown by much lower cell proliferative rates and increased cell loss. Therefore, the relatively slow net tumor growth rate in the presence of an intact nocturnal circadian melatonin signal reflects an overall balance in tumor circadian dynamics characterized by a up-regulation of daytime metabolism, signaling, proliferation and cell survival offset by a highly significant down-regulation of these activities during the nighttime (Blask et al 2014). …”

Melatonin, an inhibitory agent in breast cancer

“…hemostasis [58], the ribosome biogenesis suppression [59], inhibition of cAMP formation, induction of p53, and p21 upregulation. Additionally it seems that the suppression of linoleic acid uptake and its conversion to 13-hydroxyoctadexadienoic acid (13-HODE), associated with the reduction of breast cancer cells metabolism through melatonin treatment may boost the melatonin anti proliferative effects [12,29,60].…”

Melatonin-Induced Oncostasis, Mechanisms and Clinical Relevance

“…Therefore, some antitumor effects of melatonin correlate with melatonin receptor (MT 1 / MT 2 )-dependent inhibition of linoleic acid uptake [89]. In addition, melatonin could suppress the Warburg effect by reducing 13-HODE formation and thus activation of AKT, which is a major stimulatory pathway for aerobic glycolysis [92]. …”