Cleaved caspase-3 transcriptionally regulates angiogenesis-promoting chemotherapy resistance

Antoine Bernard, Sandy Chevrier, Françoise Beltjens, Magalie Dosset, Etienne Viltard, Anais Lagrange, Valentin Derangere, Alexandra Oudot, François Ghiringhelli, Bertrand Collin, Lionel Apetoh, Olivier Feron, Suzie Chen, Laurent Arnould, Frederique Vegran, Romain Boidot

Research output: Contribution to journalArticle

4 Scopus citations

Abstract

Caspases are well known for their role in apoptosis. Recently, nonapoptotic roles of caspases have been identified, however, these noncanonical roles are not well documented and the mechanisms involved are not fully understood. Here, we studied the role of cleaved caspase-3 using human- and mouse-proficient caspase-3 cancer cell lines and human-deficient caspase-3 cancer cells. Cleaved caspase-3 functioned as a transcription factor and directly bound to DNA. A DNA-binding domain was identified in the small subunit of caspase-3 and an active conformation was essential for caspase-3 transcriptional activity. Caspase-3 DNA binding enhanced angiogenesis by upregulating the expression of proangiogenic genes and by activating pathways that promoted endothelial cell activation. Some proapoptotic genes were downregulated in caspase-3–proficient cells. Inhibiting caspase-3 increased the efficacy of chemotherapy and decreased spontaneous tumor development. These data highlight a novel nonapoptotic role of caspase-3 and suggest that cleaved caspase-3 could be a new therapeutic target in cancer. Significance: These findings report a noncanonical function of caspase-3 by demonstrating its ability to transcrip-tionally regulate the VEGFR pathway.

Original languageEnglish (US)
Pages (from-to)5958-5970
Number of pages13
JournalCancer Research
Volume79
Issue number23
DOIs
StatePublished - Dec 1 2019

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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