Caspase-3 enhances lung metastasis and cell migration in a protease-independent mechanism through the ERK pathway.
Caspase-3 is known as a cysteine protease that primarily executes the cell death program. However, some tumors express higher levels of caspase-3 in positive correlation with malignancy. Here, we showed that caspase-3 can promote tumor metastasis in a protease-independent mechanism. Ectopic expression of caspase-3 enhanced lung metastasis and cell motility of caspase-3 deficient MCF-7 cells. By contrast, caspase-3 siRNA reduced the invasiveness and metastasis ability of A549 cells that express high level of caspase-3. Moreover, caspase-3 induced ERK activation. Alteration of caspase-3 by introducing non-processable mutation at its cleavage site or treatment of caspase-3 inhibitor did not diminish the caspase-3-associated increases in ERK phosphorylation and cell migration. Confocal microscopy study showed that caspase-3 was not physically associated with ERK. Inhibiting ceramide formation by blockage of the ceramide synthase or acid sphingomyelinase activity resulted in significant reduction of ERK phosphorylation and cell migration. In summary, caspase-3 induces ERK activation through a ceramide-dependant, protease activity-independent mechanism, which represents a novel role of caspase-3 in tumor metastasis.
Cheng
Yu-Jung
YJ
Department of Microbiology and Immunology, National Cheng Kung University, Tainan 70428, Taiwan.
Lee
Chien-Hsin
CH
Lin
Yu-Ping
YP
Huang
Jyun-Yuan
JY
Su
Chung-Chen
CC
Chang
Wen-Tsan
WT
Yang
Bei-Chang
BC
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D015153:Blotting, Western; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002465:Cell Movement / Q000502:physiology; D002518:Ceramides / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005434:Flow Cytometry; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000201:enzymology*; D051379:Mice; D008819:Mice, Nude; D018613:Microscopy, Confocal; D009361:Neoplasm Invasiveness / Q000235:genetics; D009362:Neoplasm Metastasis / Q000235:genetics; D010447:Peptide Hydrolases / Q000378:metabolism*; D010766:Phosphorylation; D034741:RNA, Small Interfering; D013108:Sphingomyelin Phosphodiesterase / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D002518:Ceramides; D034741:RNA, Small Interfering; D048049:Extracellular Signal-Regulated MAP Kinases; D013108:Sphingomyelin Phosphodiesterase; D010447:Peptide Hydrolases; D053148:Caspase 3