A metabolic oscillator controls temporal changes in lipid metabolism and redox status in tumor cells.

MONJES, NATALIA M.; WAGNER, PAULA M.; GUIDO, MARIO E.

Carlos Paz, Córdoba

Congreso; SAN, Sociedad Argentina de investigaciones en Neurociencias; 2019

Biological clocks even present in immortalized cell lines, regulate physiological processes in a time-dependent manner, driving transcriptional and metabolic rhythms. The molecular clock controls the expression of activators (BMAL1), repressors (PER1, 2, REV-ERB) and clock-controlled genes (Choline Kinase) along 24hs. REV-ERBs are involved in tumorigenesis and its synthetic agonist SR9009 affects the metabolism and cell viability in vivo. The disruption of circadian rhythmicity in modern life (ex. shiftwork, jetlag) may promote higher cancer risk and metabolic disorders, but little is known about the biological clock function in tumor cells. Here we studied metabolic rhythms and its link with the molecular clock in two models of human tumor cell lines: the glioblastoma T98G and hepatocarcinoma HepG2 cells. In T98G cells we observed rhythms on redox state and glycerophospholipids (GPLs) metabolisms. Also, the temporal changes in the redox cycles were altered after Bmal1 knock-down. SR9009 treated cells exhibited increased lipid droplets (LDs) levels and decreased ROS and proliferation. HepG2 cells displayed significant circadian rhythms in the content of clock genes and CHOK proteins, in the ratio of endogenous GPLs (PC and PE) and in LDs levels. When the circadian clock was damped LDs and CHOK protein rhythms were damped out. Our results suggest a significant cross-talk between the molecular and the metabolic clocks in proliferating tumor cells from either, brain and liver.