title: 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.
authors.affiliation: Department of Oncological Sciences, University of Utah and Huntsman Cancer Institute, Salt Lake City, UT 84112, USA.
authors.forename: M R
authors.initials: MR
authors.lastname: Terry
authors.affiliation: Department of Oncological Sciences, University of Utah and Huntsman Cancer Institute, Salt Lake City, UT 84112, USA.
authors.forename: R
authors.initials: R
authors.lastname: Arya
authors.affiliation: Department of Oncological Sciences, University of Utah and Huntsman Cancer Institute, Salt Lake City, UT 84112, USA.
authors.forename: A
authors.initials: A
authors.lastname: Mukhopadhyay
authors.affiliation: Department of Oncological Sciences, University of Utah and Huntsman Cancer Institute, Salt Lake City, UT 84112, USA.
authors.forename: K C
authors.initials: KC
authors.lastname: Berrett
authors.affiliation: Department of Oncological Sciences, University of Utah and Huntsman Cancer Institute, Salt Lake City, UT 84112, USA.
authors.forename: P M
authors.initials: PM
authors.lastname: Clair
authors.affiliation: 1] Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT 84112, USA [2] Associated Regional University Pathologists (ARUP) Institute for Clinical & Experimental Pathology, ARUP Laboratories, Salt Lake City, UT 84108, USA.
authors.forename: B
authors.initials: B
authors.lastname: Witt
authors.affiliation: 1] Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT 84112, USA [2] Associated Regional University Pathologists (ARUP) Institute for Clinical & Experimental Pathology, ARUP Laboratories, Salt Lake City, UT 84108, USA.
authors.forename: M E
authors.initials: ME
authors.lastname: Salama
authors.affiliation: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: A
authors.initials: A
authors.lastname: Bhutkar
authors.affiliation: Department of Oncological Sciences, University of Utah and Huntsman Cancer Institute, Salt Lake City, UT 84112, USA.
authors.forename: T G
authors.initials: TG
authors.lastname: Oliver
mesh_terms: D000818:Animals; D053143:Caspase 2 / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003546:Cysteine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D051379:Mice; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D015398:Signal Transduction
chemical_list: D009363:Neoplasm Proteins; C490360:CASP2 protein, human; C090208:Casp2 protein, mouse; D053143:Caspase 2; D003546:Cysteine Endopeptidases