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Published on: February 6, 2015
Caspase-2 impacts lung tumorigenesis and chemotherapy response in vivo
M R Terry1, R Arya1, A Mukhopadhyay1
1Department of Oncological Sciences, University of Utah and Huntsman Cancer Institute, Salt Lake City, UT 84112, USA.
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.
Insights
Caspase-2 acts as a tumor suppressor in lung cancer by regulating p53 stability. Its loss accelerates tumor growth but initially enhances chemotherapy sensitivity, followed by rapid rebound, impacting long-term treatment success.
Area of Science:
- Molecular Biology
- Oncology
- Cancer Research
Background:
- Caspase-2, an atypical caspase, regulates key cellular processes like apoptosis and genome maintenance.
- Its role in lung cancer chemotherapy response remains unclear, particularly in vivo.
- Understanding Caspase-2's function is crucial for developing effective cancer therapies.
Purpose of the Study:
- To investigate the in vivo role of Caspase-2 in Kras-driven lung cancer.
- To elucidate the molecular mechanisms underlying Caspase-2's function in tumorigenesis and chemotherapy response.
- To explore the relationship between Caspase-2, Mdm2, and p53 in lung cancer.
Main Methods:
- In vivo studies using Kras-driven lung cancer models.
- Analysis of tumor proliferation, progression, and response to chemotherapy.
- Molecular analyses including Western blotting and gene expression profiling to assess protein stability and target gene regulation.
Main Results:
- Caspase-2 functions as a tumor suppressor in Kras-driven lung cancer, with its loss promoting tumor proliferation.
- Caspase-2-deficient tumors show initial sensitivity to chemotherapy but exhibit rapid rebound and enhanced proliferation.
- Caspase-2 directly cleaves and inhibits Mdm2, stabilizing the tumor suppressor p53, a mechanism reduced in human lung tumors.
Conclusions:
- Caspase-2 plays a critical role in regulating lung tumorigenesis and chemotherapy response through the Mdm2/p53 signaling pathway.
- The Caspase-2-p53 network is a potential therapeutic target for improving lung cancer treatment outcomes.
- Understanding this pathway provides insights into tumor rebound mechanisms following chemotherapy.
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