TEMPORAL CONTROL OF TUMOR GROWTH IN NOCTURNAL MAMMALS: IMPACT OF THE CIRCADIAN SYSTEM

PRUCCA, C.G.; WAGNER, PM.; SUAREZ, T.; VELAZQUEZ, F.; CAPUTTO, BL; GUIDO, ME

Salta

Congreso; LV Annual SAIB Meeting and XIV PABMB Congress; 2019

SAIB- PABMB

Perturbations of the circadian clock function have a profound impact on numerous cellular pathways and thereby likely to contribute to many of the hallmarks of cancer. It has been proposed that the misalignment between the endogenous circadian clock and external time is correlated with increased cancer risk. However, little is known about the circadian clock function during tumorigenesis. Here we investigate the day/night differences in the growth rate of peripheral nervous system tumors generated after the injection of A530 cells isolated from NPcis (Trp53+/-; Nf1+/-) heterozygous mice. First, synchronized A530 cultures exhibited temporal fluctuations in PER1 protein and ROS (Reactive Oxygen Species) levels as well as in their susceptibility to Bortezomib chemotherapy (a well-known proteasome inhibitor). Secondly, A530 or B16 melanoma cells injected on C57BL/6 mice at the beginning of the day or the night showed differences in the tumor growth rate being higher when mice were injected at night as compared with those injected at the beginning of the day in animals maintained in a 12:12 LD regular cycle. This phenomenon was also observed in mice released to constant dark after LD synchronization and injected at the beginning of subjective day or night. Lastly, when we examined the role of the molecular clock activator Bmal1, a higher tumor growth rate was observed in mice injected with cells (A530 A5) in which Bmal1 expression was diminished by CRISPR/Cas9 compared with controls. Our observations strongly suggest an important circadian regulation on tumor growth mainly dependent on the host state.