EXPLORING THE CONNECTION BETWEEN CIRCADIAN RHYTHMS AND LIPID METABOLISM IN A GLIOBLASTOMA CELL MODEL

FORNASIER SJ; SUÁREZ AI; WAGNER PM; PRUCCA CG; GUIDO ME

Córdoba

Congreso; LX Annual Meeting of the Argentine Society for Biochemistry and Molecular Biology Research (SAIB); 2024

The circadian clock temporally regulates physiology enabling the adaptation of living organisms to the 24 h day/nightcycle. At a cellular level, this clock is composed of the transcriptional machinery and the metabolic/cytosolic oscillator,which work together on the regulation of several processes. Circadian disruption often results from modern lifestyleand is linked to various health conditions, including metabolic disorders and cancer. Carcinogenesis involves thederegulation of cell growth and division and the reprogramming of cell metabolism. Little is known about the impactof the circadian system on cancer progression and response to therapies. However, previous results from our laboratoryevidence that different tumor cells keep a functional clock and show different responses to chemotherapy across thecircadian range, suggesting that the clock may control tumor growth and therapeutic efficacy in a temporal manner. Inaddition, choline kinase alpha (CHKA), a key enzyme in phosphatidylcholine synthesis, has been reported to beoverexpressed in different tumors, being proposed as a novel therapeutic target. Results from our laboratory also showthat CHKA expression is regulated by the clock. Glioblastoma (GBM) is the most frequent and aggressive cancer ofthe central nervous system. Its standard treatment involves surgical removal followed by radiation and chemotherapywith temozolomide. The overall survival for patients under this treatment is around 15 months from the diagnosis ofGBM, with a frequent resistance to therapy. Therefore, new therapeutic approaches are needed, also considering theimpact of the circadian clock. Our aim is to further investigate the role of the clock and its relationship with lipidmetabolism in cancer, using GL26 cells, a murine cell model of GBM. These cells have not been previouslycharacterized from the circadian insight. Our results show that GL26 cells display rhythms in the expression of thetranscriptional clock proteins BMAL1 and REV-ERBs. Moreover, these cells exhibit metabolic oscillations in the sizeand number of lipid droplets, reflecting that their transcriptional and metabolic oscillators are both functional. In orderto study the role of CHKA in GBM progression, we generated a CHKA knocked-down (KD) GL26 model by CRISPRCas9. Preliminary results show that CHKA KD cells have a lower proliferation rate compared to wild-type cells,indicating that CHKA may be relevant for tumor growth. Looking at cancer biology from a chronobiologicalperspective would allow us to improve therapeutic strategies, ultimately leading to better outcomes for GBM patients.