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Caspase-2 impacts lung tumorigenesis and chemotherapy response in vivo.

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.
AuthorsM R Terry, R Arya, A Mukhopadhyay, K C Berrett, P M Clair, B Witt, M E Salama, A Bhutkar, T G Oliver
JournalCell death and differentiation (Cell Death Differ) Vol. 22 Issue 5 Pg. 719-30 (May 2015) ISSN: 1476-5403 [Electronic] England
PMID25301067 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • Neoplasm Proteins
  • CASP2 protein, human
  • Casp2 protein, mouse
  • Caspase 2
  • Cysteine Endopeptidases
Topics
  • Animals
  • Caspase 2 (genetics, metabolism)
  • Cell Line, Tumor
  • Cell Proliferation
  • Cysteine Endopeptidases (genetics, metabolism)
  • Humans
  • Lung Neoplasms (drug therapy, enzymology, genetics, pathology)
  • Mice
  • Neoplasm Proteins (genetics, metabolism)
  • Neoplasms, Experimental (drug therapy, enzymology, genetics, pathology)
  • Signal Transduction

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