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.
Highlights
Renewed interest in the metabolism of cancer growth [1,2,3] has recently led to an intensive re-evaluation of the role played by aerobic glycolysis in malignant growth progression [4]
Plasma total fatty acids (TFAs) (Fig. 1B) and linoleic acid (LA) (Fig. 1C) rhythms in LD controls, which are dependent upon circadian suprachiasmatic nucleus (SCN)-driven nocturnal feeding activity, were preserved in light at night (LAN)-exposed rats indicating that circadian disruption was limited to suppression of the nocturnal melatonin signal
Circulating insulin levels exhibited a daily oscillation under LD 12:12 (Fig. 1F) that generally mirrored the pattern of circulating insulin-like growth factor-1 (IGF-1) concentrations previously reported [28]
Summary
Renewed interest in the metabolism of cancer growth [1,2,3] has recently led to an intensive re-evaluation of the role played by aerobic glycolysis (e.g., the Warburg effect) in malignant growth progression [4]. In many tumors, including human cancer xenografts [9,11,12], 13-HODE exerts a positive feedback effect on EGF and IGF-1 receptor growth signaling pathways to enhance downstream phosphorylation of ERK1/2 and AKT leading to amplified cell proliferation and survival responses [15]. It must be noted, that in some other cancer model systems and experimental contexts 13-HODE may play an antiproliferative role [16]
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