Involvement of endoplasmic reticulum in paclitaxel-induced apoptosis.
The participation of the mitochondrial pathway in paclitaxel-induced apoptosis has been well documented. After addition of paclitaxel to U937 cells, however, we observed an early expression of five endoplasmic reticulum (ER) stress response genes that preceded the release of cytochrome c from the mitochondria and the cleavage of the caspases. Involvement of the ER was supported by the following evidence. Paclitaxel treatment not only activated calpain and caspase-4, but also induced a gradual increase in the cytosolic Ca(2+) concentration at 3-6 h. Paclitaxel-induced apoptosis can be inhibited by the calpain inhibitor calpeptin and IP(3) receptor inhibitors. Either buffering of the cytosolic Ca(2+) or inhibition of mitochondrial calcium uptake reduced BiP expression. These inhibitors also reduced mitochondrial apoptotic signals, such as mitochondrion membrane potential disruption, cytochrome c release and eventually reduced the death of U937 cells. Paclitaxel-induced Bax/Bak translocation to the ER and Bax dimerization on the ER membrane occurred within 3 h, which led to a Ca(2+) efflux into cytosol. Moreover, we found that cytochrome c translocated to the ER after releasing from mitochondria and then interacted with the IP(3) receptor at 12-15 h. This phenomenon has been known to amplify apoptotic signaling. Taken together, ER would seem to contribute to paclitaxel-induced apoptosis via both the early release of Ca(2+) and the late amplification of mitochondria-mediated apoptotic signals.
Liao
Pei-Chun
PC
Department of Biotechnology and Laboratory Science in Medicine, School of Biomedical Science and Engineering, National Yang-Ming University, Taipei, Taiwan 112, Republic of China.
Tan
Sai-Koong
SK
Lieu
Chien-Hui
CH
Jung
Hsuan-Kuang
HK
D017209:Apoptosis / Q000187:drug effects*; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D004721:Endoplasmic Reticulum / Q000502:physiology*; D006801:Humans; D024101:Mitochondrial Proteins / Q000502:physiology; D017239:Paclitaxel / Q000494:pharmacology*; D015398:Signal Transduction
D024101:Mitochondrial Proteins; D017239:Paclitaxel; D002118:Calcium