CDK4/6 inhibitor-mediated cell overgrowth triggers osmotic and replication stress to promote senescence
Journal: Molecular cell (2023)
Institution: University of Dundee
Research Areas: Cancer Research
Cell Lines: hTERT-RPE1 mRuby-PCNA, hTERT-RPE1-FUCCI, MCF7
Summary: Abnormal increases in cell size are associated with senescence and cell cycle exit. The mechanisms by which overgrowth primes cells to withdraw from the cell cycle remain unknown.The authors address this question using CDK4/6 inhibitors, which arrest cells in G0/G1 and are licensed to treat advanced HR+/HER2− breast cancer. They demonstrate that CDK4/6-inhibited cells overgrow during G0/G1, causing p38/p53/p21-dependent cell cycle withdrawal. Cell cycle withdrawal is triggered by biphasic p21 induction. The first p21 wave is caused by osmotic stress, leading to p38- and size-dependent accumulation of p21. CDK4/6 inhibitor washout results in some cells entering S-phase. Overgrown cells experience replication stress, resulting in a second p21 wave that promotes cell cycle withdrawal from G2 or the subsequent G1. The authors propose that the levels of p21 integrate signals from overgrowth-triggered stresses to determine cell fate. This model explains how hypertrophy can drive senescence and why CDK4/6 inhibitors have long-lasting effects in patients.HoloMonitor M4 was used to study the cell volume change with CDK4/6i treatment.