Dataset Information

CDK4/6 inhibitor-mediated cell overgrowth triggers an osmotic stress response

ABSTRACT: Cell size and the cell cycle are intrinsically coupled and abnormal increases in cell size are associated with senescence and permanent cell cycle arrest. The mechanism by which overgrowth primes cells to withdraw from the cell cycle remains unknown. We investigate this here using CDK4/6 inhibitors that arrest cell cycle progression during G0/G1 and are used in the clinic to treat ER+/HER2- metastatic breast cancer. We demonstrate that CDK4/6 inhibition promotes cellular overgrowth during G0/G1, causing p38MAPK-p53-p21-dependent cell cycle withdrawal. We find that cell cycle withdrawal is triggered by two waves of p21 induction. First, overgrowth during a long-term G0/G1 arrest induces an osmotic stress response. This stress response produces the first wave of p21 induction. Second, when CDK4/6 inhibitors are removed, a fraction of cells escape long term G0/G1 arrest and enter S-phase where overgrowth-driven replication stress results in a second wave of p21 induction that causes cell cycle withdrawal from G2, or the subsequent G1. We propose a model whereby both waves of p21 induction contribute to promote permanent cell cycle arrest. This model could explain why cellular hypertrophy is associated with senescence and why CDK4/6 inhibitors have long-lasting effects in patients.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Epithelial Cell

SUBMITTER: Tony Ly

LAB HEAD: Tony Ly

PROVIDER: PXD036519 | Pride | 2023-11-27

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	E201105_02_Exploris_VK_160_WT_D4_PD-1.raw	Raw
	E201105_02_Exploris_VK_180_WT_D4_PD-1.raw	Raw
	E201105_04_Exploris_VK_180_WT_D7_PD-2.raw	Raw
	E201105_06_Exploris_VK_180_WT_G1_control_-2.raw	Raw
	E201105_08_Exploris_VK_180_WT_D2_PD-2.raw	Raw

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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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