Caspase-2 impacts lung tumorigenesis and chemotherapy response in vivo

M. R. Terry, R. Arya, A. Mukhopadhyay, K. C. Berrett, P. M. Clair, B. Witt, M. E. Salama, A. Bhutkar, T. G. Oliver

Research output: Contribution to journalArticle

21 Scopus citations

Abstract

Caspase-2 is an atypical caspase that regulates apoptosis, cell cycle arrest and genome maintenance, although the mechanisms are not well understood. Caspase-2 has also been implicated in chemotherapy response in lung cancer, but this function has not been addressed in vivo. Here we show that Caspase-2 functions as a tumor suppressor in Kras-driven lung cancer in vivo. Loss of Caspase-2 leads to enhanced tumor proliferation and progression. Despite being more histologically advanced, Caspase-2-deficient tumors are sensitive to chemotherapy and exhibit a significant reduction in tumor volume following repeated treatment. However, Caspase-2-deficient tumors rapidly rebound from chemotherapy with enhanced proliferation, ultimately hindering long-term therapeutic benefit. In response to DNA damage, Caspase-2 cleaves and inhibits Mdm2 and thereby promotes the stability of the tumor-suppressor p53. Caspase-2 expression levels are significantly reduced in human lung tumors with wild-type p53, in agreement with the model whereby Caspase-2 functions through Mdm2/p53 regulation. Consistently, p53 target genes including p21, cyclin G1 and Msh2 are reduced in Caspase-2-deficient tumors. Finally, we show that phosphorylation of p53-induced protein with a death domain 1 leads to Caspase-2-mediated cleavage of Mdm2, directly impacting p53 levels, activity and chemotherapy response. Together, these studies elucidate a Caspase-2-p53 signaling network that impacts lung tumorigenesis and chemotherapy response in vivo.

Original languageEnglish (US)
Pages (from-to)719-730
Number of pages12
JournalCell Death and Differentiation
Volume22
Issue number5
DOIs
StatePublished - Apr 1 2015

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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  • Cite this

    Terry, M. R., Arya, R., Mukhopadhyay, A., Berrett, K. C., Clair, P. M., Witt, B., Salama, M. E., Bhutkar, A., & Oliver, T. G. (2015). Caspase-2 impacts lung tumorigenesis and chemotherapy response in vivo. Cell Death and Differentiation, 22(5), 719-730. https://doi.org/10.1038/cdd.2014.159