Language

English

Publication Date

7-1-2026

Journal

Journal of Biological Chemistry

DOI

10.1016/j.jbc.2026.113199

PMID

42208898

PMCID

PMC13320034

PubMedCentral® Posted Date

5-27-2026

PubMedCentral® Full Text Version

Post-print

Abstract

Caspase-2 has positive and negative effects on tumor growth in different cancer models. The mechanisms determining these dual outcomes of caspase-2 activation are unclear underscoring the need to assess caspase-2 function in different cell types. We report that high caspase-2 expression is associated with lower survival in patients with colon cancer and increased tumor size in HCT116 colon cancer xenografts. We investigated the interplay between caspase-2 and p53 in regulating the proliferation of these cells. While neither of these proteins had much of an effect on cell cycle arrest on their own, deficiency in both caspase-2 and p53 led to slower proliferation, prolonged G1 cell cycle arrest, and impaired homologous recombination. Caspase-2 loss resulted in increased p53 transcription and activation, while p53 loss resulted in increased caspase-2 activation suggesting that these two proteins compensate for each other. Strikingly, loss of caspase-2 led to disruption of p53-dependent transcription and enhanced the ability of p53 to bind to the promoter regions of the genes encoding mouse and human double minute 2 and p21. These results were unique to the HCT116 cells, but activation of the WNT pathway in RKO, a second colon cancer cell line, caused them to phenocopy HCT116 cells with respect to the requirement for caspase-2 and p53 for the DNA damage response. Our data support a model in which caspase-2 and p53 can compensate for the loss of each other to ensure cell cycle and homologous recombination proceed correctly. Together, our data suggest that inhibiting both proteins would be detrimental to colon cancer cell growth.

Keywords

Humans, Caspase 2, Tumor Suppressor Protein p53, DNA Damage, HCT116 Cells, Colonic Neoplasms, Animals, Mice, Cell Proliferation, Cysteine Endopeptidases

Published Open-Access

yes

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