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.