Wang Xiu-Fang, Birringer Marc, Dong Lan-Feng, Veprek Pavel, Low Pauline, Swettenham Emma, Stantic Marina, Yuan Lin-Hong, Zobalova Renata, Wu Kun, Ledvina Miroslav, Ralph Stephen J, Neuzil Jiri
Apoptosis Research Group and Genomics Research Centre, School of Medical Science, Griffith University, Southport, Queensland, Australia.
Cancer Res. 2007 Apr 1;67(7):3337-44. doi: 10.1158/0008-5472.CAN-06-2480.
Overexpression of erbB2 is associated with resistance to apoptosis. We explored whether high level of erbB2 expression by cancer cells allows their targeting using an erbB2-binding peptide (LTVSPWY) attached to the proapoptotic alpha-tocopheryl succinate (alpha-TOS). Treating erbB2-low or erbB2-high cells with alpha-TOS induced similar levels of apoptosis, whereas alpha-TOS-LTVSPWY induced greater levels of apoptosis in erbB2-high cells. alpha-TOS rapidly accumulated in erbB2-high cells exposed to alpha-TOS-LTVSPWY. The extent of apoptosis induced in erbB2-high cells by alpha-TOS-LTVSPWY was suppressed by erbB2 RNA interference as well as by inhibition of either endocytotic or lysosomal function. alpha-TOS-LTVSPWY reduced erbB2-high breast carcinomas in FVB/N c-neu transgenic mice. We conclude that a conjugate of a peptide targeting alpha-TOS to erbB2-overexpressing cancer cells induces rapid apoptosis and efficiently suppresses erbB2-positive breast tumors.
erbB2的过表达与细胞凋亡抗性相关。我们探究了癌细胞中高水平的erbB2表达是否能使其通过连接促凋亡的α-生育酚琥珀酸酯（α-TOS）的erbB2结合肽（LTVSPWY）进行靶向作用。用α-TOS处理erbB2低表达或erbB2高表达细胞诱导出相似水平的细胞凋亡，而α-TOS-LTVSPWY在erbB2高表达细胞中诱导出更高水平的细胞凋亡。α-TOS在暴露于α-TOS-LTVSPWY的erbB2高表达细胞中迅速积累。erbB2 RNA干扰以及对胞吞或溶酶体功能的抑制均抑制了α-TOS-LTVSPWY在erbB2高表达细胞中诱导的细胞凋亡程度。α-TOS-LTVSPWY缩小了FVB/N c-neu转基因小鼠中erbB2高表达的乳腺癌。我们得出结论，将靶向α-TOS的肽与erbB2过表达癌细胞结合可诱导快速细胞凋亡并有效抑制erbB2阳性乳腺肿瘤。
