Oncogenic and Circadian Effects of Small Molecules Directly and Indirectly Targeting the Core Circadian Clock

Abstract

Circadian rhythms are essential for controlling the cell cycle, cellular proliferation, and apoptosis, and hence are tightly linked to cell fate. Several recent studies have used small molecules to affect circadian oscillations; however, their concomitant cellular effects were not assessed, and they have not been compared under similar experimental conditions. In this work, we use five molecules, grouped into direct versus indirect effectors of the circadian clock, to modulate periods in a human osteosarcoma cell line (U2OS) and determine their influences on cellular behaviors, including motility and colony formation. Luciferase reporters, whose expression was driven via Bmal1- or Per2-promoters, were used to facilitate the visualization and quantitative analysis of circadian oscillations. We show that all molecules increase or decrease the circadian periods of Bmal1 and Per2 in a dose-dependent manner, but period length does not correlate with the extent of cell migration or proliferation. Nonetheless, molecules that affected circadian oscillations to a greater degree resulted in substantial influence on cellular behaviors (ie, motility and colony formation), which may also be attributable to noncircadian targets. Furthermore, we find that the ability and extent to which the molecules are able to affect oscillations is independent of whether they are direct or indirect modulators. Because of the numerous connections and feedback between the circadian clock and other pathways, it is important to consider the effects of both in assessing these and other compounds.

Pharmacological modulation of the cytosolic oscillator affects glioblastoma cell biology

“…By contrast, no significant differences were observed in the percentage of wound closure between cultures treated with PF670462 (1.5 μM) or KL001 (25.4 μM) and control cells. In this connection, Lin and collaborators showed that KL001 (12 μM) or PF670462 (1.5 μM) treatment for 24 h did not significantly affect cancer cell migration compared to osteosarcoma non-treated cells [52]. Reports in the literature support our results, suggesting that GSK-3 has a key role in regulating epithelialmesenchymal transition (EMT) in prostate and bladder tumors (reviewed in [28]).…”

Pharmacological Modulation of the Cytosolic Oscillator Affects Glioblastoma Cell Biology

“…By contrast, no significant differences were observed in the percentage of wound closure between cultures treated with PF670462 (1.5 μM) or KL001 (25.4 μM) and control cells. In this connection, Lin and collaborators showed that KL001 (12 μM) or PF670462 (1.5 μM) treatment for 24 h did not significantly affect cancer cell migration compared to osteosarcoma non-treated cells (Lin et al 2020 ). Reports in the literature support our results, suggesting that GSK-3 has a key role in regulating epithelial-mesenchymal transition (EMT) in prostate and bladder tumors (reviewed in (Sahin et al 2019 )).…”

When the clock ticks wrong with COVID‐19

“…Accumulation of PER and CRY and their heterodimerization in the evening prevent the activity of BMAL1 and CLOCK. Therefore, a rhythmic oscillation occurs within a period of about 24 h 36 …”

“…35 Accumulation of PER and CRY and their heterodimerization in the evening prevent the activity of BMAL1 and CLOCK. Therefore, a rhythmic oscillation occurs within a period of about 24 h. 36 The circadian clock is involved in regulating many physiological processes in the body. 37 A healthy individual has a synchronized circadian clock system working in harmony between the central and peripheral clocks.…”