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.
Subject(s)
Caspase 2/metabolism , Cysteine Endopeptidases/metabolism , Lung Neoplasms , Neoplasm Proteins/metabolism , Neoplasms, Experimental , Signal Transduction , Animals , Caspase 2/genetics , Cell Line, Tumor , Cell Proliferation , Cysteine Endopeptidases/genetics , Humans , Lung Neoplasms/drug therapy , Lung Neoplasms/enzymology , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Mice , Neoplasm Proteins/genetics , Neoplasms, Experimental/drug therapy , Neoplasms, Experimental/enzymology , Neoplasms, Experimental/genetics , Neoplasms, Experimental/pathologyABSTRACT
The lethal and incapacitating effects of the toxic organophosphorus (OP) agent, soman were evaluated in guinea pigs. The protective effects of the standard therapies atropine sulfate (ATR) and pralidoxime chloride (2-PAM) in minimizing or reducing soman-produced lethality and incapacitation (evaluated using a modification of the rat conditioned avoidance procedure) were also studied. At 0.75 and 1.5 LD50 soman was extremely toxic and fast-acting; its effects appeared within five minutes, and its lethal effects occurred within the first three hours. Therapeutic combinations of ATR (64 or 128 mg/kg) and 2-PAM (25 or 100 mg/kg) protected animals from the lethality of soman, but not from its incapacitating effects. However, therapeutic treatment with ATR and 2-PAM also produced a behavioral toxicity in its own right, an effect which lasted for at least three hours in the guinea pig. This behavioral toxicity was lessened by reducing ATR dosage from 128 to 64 mg/kg, but 2-PAM dosage did not influence the behavioral toxicity of the treatment combinations within the range of dosages studied.
