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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.

SUBMITTER: Terry MR

PROVIDER: S-EPMC4392070 | biostudies-literature | 2015 May

REPOSITORIES: biostudies-literature

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

Terry M R MR Arya R R Mukhopadhyay A A Berrett K C KC Clair P M PM Witt B B Salama M E ME Bhutkar A A Oliver T G TG

Cell death and differentiation 20141010 5

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-d ...[more]

PMID: 25301067

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Project description:Colorectal cancer (CRC) is one of the most common cancers in the Western world. 5-Fluorouracil (5FU)-based chemotherapy (CT) remains the mainstay treatment of CRC in the advanced setting, and activates executioner caspases in target cells. Executioner caspases are key proteins involved in cell disassembly during apoptosis. Activation of executioner caspases also has a role in tissue regeneration and repopulation by stimulating signal transduction and cell proliferation in neighbouring, non-apoptotic cells as reported recently. Tissue microarrays (TMAs) consisting of tumour tissue from 93 stage II and III colon cancer patients were analysed by immunohistochemistry. Surprisingly, patients with low levels of active Caspase-3 had an increased disease-free survival time. This was particularly pronounced in patients who received 5FU-based adjuvant CT. In line with this observation, lower serum levels of active Caspase-3 were found in patients with metastasised CRC who revealed stable disease or tumour regression compared with those with disease progression. The role of Caspase-3 in treatment responses was explored further in primary human tumour explant cultures from fresh patient tumour tissue. Exposure of explant cultures to 5FU-based CT increased the percentage of cells positive for active Caspase-3 and Terminal Deoxynucleotidyl Transferase dUTP Nick end Labelling (TUNEL), but also the expression of regeneration and proliferation markers β-Catenin and Ki-67, as well as cyclooxygenase-2 (COX-2). Of note, selective inhibition of Caspase-3 with Ac-DNLD-CHO, a selective, reversible inhibitor of Caspase-3, significantly reduced the expression of proliferation markers as well as COX-2. Inhibition of COX-2 with aspirin or celecoxib did not affect Caspase-3 levels but also reduced Ki-67 and β-Catenin levels, suggesting that Caspase-3 acted via COX-2 to stimulate cell proliferation and tissue regeneration. This indicates that low levels of active Caspase-3 may represent a new predictor of CT responsiveness, and inhibition of Caspase-3, or antagonising downstream effectors of Caspase-3 paracrine signalling, such as COX-2 may improve patient outcomes following CT in advanced CRC.

Dataset Information

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

Publications

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

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