Calpain inhibition stimulates caspase-dependent apoptosis induced by taxol in NIH3T3 cells.
Taxol is an anticancer drug that triggers apoptosis in a wide spectrum of cancers such as ovarian, breast, lung, head and neck, and bladder carcinoma by both caspase-dependent and -independent apoptosis mechanisms. However, the exact signaling pathways involved in taxol-induced apoptosis strongly depend on the cellular background and they are not completely established yet. In this study we demonstrate that taxol induces caspase-3-independent apoptosis in NIH3T3 cells by a calpain-mediated mechanism. Taxol treatment produced changes in the mitochondrial membrane potential (Delta Psi m) which could be responsible of Ca(2+) release from the mitochondria and the consequent calpain activation. Interestingly, we show that calpain produced proteolysis of caspase-3 and demonstrate that, accordingly, calpain inhibition increased taxol-induced apoptosis. In addition, we reveal that poly (ADP-ribose) polymerase (PARP) was processed by calpain in taxol-treated cells and by caspase-3 after calpain inhibition. In conclusion, these results demonstrate for the first time that calpain could play an important role modulating taxol-induced apoptosis. Further studies are needed to address the potentiality of inducing apoptosis by a combined use of taxol and calpain inhibitors in cells with increased calpain activity.
Piñeiro
David
D
Servicio de Bioquímica-Investigación, Hospital Ramón y Cajal, Ctra Colmenar km 9,100, 28034 Madrid, Spain.
Martín
M Elena
ME
Guerra
Natalia
N
Salinas
Matilde
M
González
Víctor M
VM
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002118:Calcium / Q000032:analysis / Q000378:metabolism; D002154:Calpain / Q000037:antagonists & inhibitors / Q000502:physiology*; D053148:Caspase 3 / Q000502:physiology*; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D003593:Cytoplasm / Q000737:chemistry / Q000378:metabolism; D004151:Dipeptides / Q000494:pharmacology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D041681:NIH 3T3 Cells; D017239:Paclitaxel / Q000494:pharmacology*
D000972:Antineoplastic Agents, Phytogenic; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D004151:Dipeptides; D002154:Calpain; D053148:Caspase 3; D017239:Paclitaxel; D002118:Calcium; C058076:calpain inhibitor III