Temporal control of tumor growth in nocturnal mammals: impact of the circadian system.

PAULA M. WAGNER; CESAR G PRUCCA; FABIOLA N VELAZQUEZ; BEATRIZ CAPUTTO; MARIO E. GUIDO

Congreso; Congreso Sociedad Argentina de Investigación en Neurosciencias; 2019

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. This circadian disruption between the endogenous circadian clock and external time has been correlated with increased cancer risk. However, little is known about the circadian clock function on tumor growth regulation. Here we investigate the day/night differences in the growth rate of peripheral nervous system tumors after the injection of A530 cells isolated from NPcis (Trp53+/-; Nf1+/-) heterozygous mice. First, synchronized A530 cultures exhibited temporal fluctuations in levels of PER1 protein, levels of ROS and susceptibility to Bortezomib chemotherapy. Secondly, A530 or melanoma B16 cells injected on C57BL/6 mice at the beginning of the day or the night showed a higher tumor growth rate 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 as well as when they were 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 when Bmal1 expression was diminished by CRISPR/Cas9 in A530 cells (A5) compared with controls. Our observations strongly suggest an important circadian regulation on tumor growth mainly dependent on the host state.