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Cell overgrowth potentiates osmotic and replication stresses to promote p38/p53/p21-dependent senescence

ABSTRACT: 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. We address this question using CDK4/6 inhibitors, which arrest cells in G0/G1 and are licensed to treat advanced HR+/HER2- breast cancer. We 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. We 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.

INSTRUMENT(S): Liquid Chromatography MS - positive - hilic, Liquid Chromatography MS - negative - hilic

PROVIDER: MTBLS8698 | MetaboLights | 2025-10-24

REPOSITORIES: MetaboLights

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CDK4/6 inhibitor-mediated cell overgrowth triggers osmotic and replication stress to promote senescence.

Crozier Lisa L Foy Reece R Adib Rozita R Kar Ananya A Holt Jordan A JA Pareri Aanchal U AU Valverde Juan M JM Rivera Rene R Weston William A WA Wilson Rona R Regnault Clement C Whitfield Phil P Badonyi Mihaly M Bennett Laura G LG Vernon Ellen G EG Gamble Amelia A Marsh Joseph A JA Staples Christopher J CJ Saurin Adrian T AT Barr Alexis R AR Ly Tony T

Molecular cell 20231116 22

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. We address this question using CDK4/6 inhibitors, which arrest cells in G0/G1 and are licensed to treat advanced HR+/HER2- breast cancer. We 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. T ...[more]

PMID: 37977118

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