TY - JOUR
T1 - Enhanced sensitization to Taxol-induced apoptosis by herceptin pretreatment in ErbB2-overexpressing breast cancer cells
AU - Lee, Sangkyou
AU - Yang, Wentao
AU - Lan, Keng Hsueh
AU - Sellappan, Shankar
AU - Klos, Kristine
AU - Hortobagyi, Gabriel
AU - Hung, Mien Chie
AU - Yu, Dihua
PY - 2002/10/15
Y1 - 2002/10/15
N2 - The recombinant humanized anti-ErbB2/HER2 monoclonal antibody Herceptin (Trastuzumab) has been shown to significantly enhance the tumoricidal effects of antitumor drugs such as paclitaxel (Taxol) in patients with ErbB2-overexpressing breast cancers. Here, we investigated the molecular mechanisms by which Herceptin enhances the antitumor effects of Taxol. Because activation of p34Cdc2 is required for Taxol-induced apoptosis and because overexpression of ErbB2 blocks Taxol-induced apoptosis by inhibiting p34Cdc2 activation, we studied the effect of Herceptin treatment on p34Cdc2 kinase activation and apoptosis in Taxol-treated human breast carcinoma cell lines MDA-MB-435, SKBr3, MDA-MB-453, and 435.eB, which is an ErbB2 transfectant of MDA-MB-435. Herceptin treatment down-regulated ErbB2, reduced the inhibitory phosphorylation of Cdc2 on Tyr-15, and down-regulated the expression of p21Cip1, a Cdc2 inhibitor. Herceptin plus Taxol treatment led to higher levels of p34Cdc2 kinase activity and apoptosis in ErbB2-overexpressing breast cancer cells, which is likely attributable to inhibition of Cdc2-Tyr-15 phosphorylation and p21Cip1 expression. Because significant dephosphorylation of Cdc2-Tyr-15 and down-regulation of p21Cip1 occur at least 24 h after Herceptin treatment, we investigated whether 24 h Herceptin pretreatment will render ErbB2-overexpressing breast cancer cells more sensitive to Taxol-induced apoptosis compared with the simultaneous treatment of Herceptin plus Taxol. Indeed, Herceptin pretreatment increased Taxol-induced apoptosis and cytotoxicity in vitro and more effectively inhibited the growth of tumor xenografts with enhanced in vivo apoptosis. Thus, Herceptin treatment of ErbB2-overexpressing cells can inhibit ErbB2-mediated Cdc2-Tyr-15 phosphorylation and p21Cip1 up-regulation, which allows effective p34Cdc2 activation and induction of apoptosis upon Taxol treatment. Herceptin pretreatment renders ErbB2-overexpressing breast cancers more susceptible to Taxol-induced cell death, which may have important clinical therapeutic implications.
AB - The recombinant humanized anti-ErbB2/HER2 monoclonal antibody Herceptin (Trastuzumab) has been shown to significantly enhance the tumoricidal effects of antitumor drugs such as paclitaxel (Taxol) in patients with ErbB2-overexpressing breast cancers. Here, we investigated the molecular mechanisms by which Herceptin enhances the antitumor effects of Taxol. Because activation of p34Cdc2 is required for Taxol-induced apoptosis and because overexpression of ErbB2 blocks Taxol-induced apoptosis by inhibiting p34Cdc2 activation, we studied the effect of Herceptin treatment on p34Cdc2 kinase activation and apoptosis in Taxol-treated human breast carcinoma cell lines MDA-MB-435, SKBr3, MDA-MB-453, and 435.eB, which is an ErbB2 transfectant of MDA-MB-435. Herceptin treatment down-regulated ErbB2, reduced the inhibitory phosphorylation of Cdc2 on Tyr-15, and down-regulated the expression of p21Cip1, a Cdc2 inhibitor. Herceptin plus Taxol treatment led to higher levels of p34Cdc2 kinase activity and apoptosis in ErbB2-overexpressing breast cancer cells, which is likely attributable to inhibition of Cdc2-Tyr-15 phosphorylation and p21Cip1 expression. Because significant dephosphorylation of Cdc2-Tyr-15 and down-regulation of p21Cip1 occur at least 24 h after Herceptin treatment, we investigated whether 24 h Herceptin pretreatment will render ErbB2-overexpressing breast cancer cells more sensitive to Taxol-induced apoptosis compared with the simultaneous treatment of Herceptin plus Taxol. Indeed, Herceptin pretreatment increased Taxol-induced apoptosis and cytotoxicity in vitro and more effectively inhibited the growth of tumor xenografts with enhanced in vivo apoptosis. Thus, Herceptin treatment of ErbB2-overexpressing cells can inhibit ErbB2-mediated Cdc2-Tyr-15 phosphorylation and p21Cip1 up-regulation, which allows effective p34Cdc2 activation and induction of apoptosis upon Taxol treatment. Herceptin pretreatment renders ErbB2-overexpressing breast cancers more susceptible to Taxol-induced cell death, which may have important clinical therapeutic implications.
UR - http://www.scopus.com/inward/record.url?scp=0037108866&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0037108866&partnerID=8YFLogxK
M3 - Article
C2 - 12384528
AN - SCOPUS:0037108866
SN - 0008-5472
VL - 62
SP - 5703
EP - 5710
JO - Cancer Research
JF - Cancer Research
IS - 20
ER -