TY - JOUR
T1 - Involvement of proapoptotic Bcl-2 family members in parthenolide-induced mitochondrial dysfunction and apoptosis
AU - Zhang, Siyuan
AU - Ong, Choon Nam
AU - Shen, Han Ming
N1 - Funding Information:
We thank Dr Z.G. Liu (NCI, NIH) for providing the CrmA expression vector. We also thank B.L. Ng for her technical assistance in flow cytometry analysis and Dr Peter Rose for his useful comments on this manuscript. This work is supported by a research grant from the National Medical Research Council, Singapore. S. Zhang is supported by a research scholarship from the National University of Singapore.
PY - 2004/8/10
Y1 - 2004/8/10
N2 - Parthenolide is a sesquiterpene lactone responsible for the bioactivities of Feverfew. Besides its potent anti-inflammatory effect, this compound has recently been reported to induce apoptosis in cancer cells, possibly through mitochondrial dysfunction. In the present study, we attempted to examine parthenolide-mediated cell death signaling pathway by focusing on the involvement of Bcl-2 family members. Using a human colorectal cancer cell line COLO205, we first demonstrated that parthenolide acted through the cell death receptor pathway to activate caspase 8. Following caspase 8 activation, Bid, a proapoptotic Bcl-2 member, was cleaved and this cleavage then triggered Bax conformational changes and Bax translocation from cytosol to mitochondrial membrane. Meanwhile, another proapoptotic protein, Bak, was up-regulated and oligomerized on the mitochondrial membrane. All these alterations were found to be prerequisite for the subsequent release of proapopototic mitochondrial proteins, including cytochrome c and Samc, in parthenolide-treated cells. Moreover, selective inhibition of caspase 8 activity by a synthetic caspase inhibitor (IETD-FMK) or overexpression of a viral protein (CrmA) suppressed the cleavage of Bid, conformational changes of Bax, cytochrome c release, and apoptosis. Therefore, the proapoptotic Bcl-2 family members are important mediators relaying the cell death signaling elicited by parthenolide from caspase 8 to downstream effector caspases such as caspase 3, and eventually to cell death.
AB - Parthenolide is a sesquiterpene lactone responsible for the bioactivities of Feverfew. Besides its potent anti-inflammatory effect, this compound has recently been reported to induce apoptosis in cancer cells, possibly through mitochondrial dysfunction. In the present study, we attempted to examine parthenolide-mediated cell death signaling pathway by focusing on the involvement of Bcl-2 family members. Using a human colorectal cancer cell line COLO205, we first demonstrated that parthenolide acted through the cell death receptor pathway to activate caspase 8. Following caspase 8 activation, Bid, a proapoptotic Bcl-2 member, was cleaved and this cleavage then triggered Bax conformational changes and Bax translocation from cytosol to mitochondrial membrane. Meanwhile, another proapoptotic protein, Bak, was up-regulated and oligomerized on the mitochondrial membrane. All these alterations were found to be prerequisite for the subsequent release of proapopototic mitochondrial proteins, including cytochrome c and Samc, in parthenolide-treated cells. Moreover, selective inhibition of caspase 8 activity by a synthetic caspase inhibitor (IETD-FMK) or overexpression of a viral protein (CrmA) suppressed the cleavage of Bid, conformational changes of Bax, cytochrome c release, and apoptosis. Therefore, the proapoptotic Bcl-2 family members are important mediators relaying the cell death signaling elicited by parthenolide from caspase 8 to downstream effector caspases such as caspase 3, and eventually to cell death.
KW - Apoptosis
KW - Bcl-2 family
KW - Mitochondria
KW - PARP, poly(ADP-ribose)polymerase
KW - PN, parthenolide
KW - Parthenolide
KW - Z-IETD-FMK, benzyloxycarbonyl-Ile-Glu-Thr-Asp-(OMe) fluoromethyl ketone
KW - z-VAD-FMK, benzyloxycarbonyl-Val-Ala-Asp-(OMe) fluoromethyl ketone
UR - http://www.scopus.com/inward/record.url?scp=3042654962&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=3042654962&partnerID=8YFLogxK
U2 - 10.1016/j.canlet.2004.03.033
DO - 10.1016/j.canlet.2004.03.033
M3 - Article
C2 - 15219941
AN - SCOPUS:3042654962
SN - 0304-3835
VL - 211
SP - 175
EP - 188
JO - Cancer Letters
JF - Cancer Letters
IS - 2
ER -