Cathepsin B mediates caspase-independent cell death induced by microtubule stabilizing agents in non-small cell lung cancer cells.
We have previously reported that the microtubule stabilizing agents (MSAs) paclitaxel, epothilone B and discodermolide induce caspase-independent cell death in non-small cell lung cancer (NSCLC) cells. Here we present two lines of evidence indicating a central role for the lysosomal protease cathepsin B in mediating cell death. First, inhibition of cathepsin B, and not of caspases or other proteases, such as cathepsin D or calpains, results in a strong protection against drug-induced cell death in several NSCLC cells. Second, MSAs trigger disruption of lysosomes and release and activation of cathepsin B. Interestingly, inhibition of cathepsin B prevents the appearance of multinucleated cells, an early characteristic of MSA-induced cell death, pointing to a central, proximal role for cathepsin B in this novel cell death pathway.
Bröker
Linda E
LE
Department of Medical Oncology, VU University Medical Center, Amsterdam, the Netherlands.
Huisman
Cynthia
C
Span
Simone W
SW
Rodriguez
José A
JA
Kruyt
Frank A E
FA
Giaccone
Giuseppe
G
D000473:Alkanes / Q000633:toxicity; D000970:Antineoplastic Agents / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects*; D001483:Base Sequence; D002219:Carbamates / Q000633:toxicity; D002289:Carcinoma, Non-Small-Cell Lung; D020169:Caspases / Q000378:metabolism*; D002401:Cathepsin B / Q000378:metabolism*; D016923:Cell Death; D017931:DNA Primers; D034261:Epothilones / Q000633:toxicity; D006801:Humans; D007783:Lactones / Q000633:toxicity; D008175:Lung Neoplasms; D008247:Lysosomes / Q000187:drug effects / Q000201:enzymology; D008856:Microscopy, Fluorescence; D008870:Microtubules / Q000187:drug effects / Q000502:physiology*; D017239:Paclitaxel / Q000633:toxicity*; D011753:Pyrones; D014162:Transfection; D014407:Tumor Cells, Cultured
D000473:Alkanes; D000970:Antineoplastic Agents; D002219:Carbamates; D017931:DNA Primers; D034261:Epothilones; D007783:Lactones; D011753:Pyrones; C071229:discodermolide; D020169:Caspases; D002401:Cathepsin B; D017239:Paclitaxel; C093788:epothilone B