Transactivator of transcription-tagged cell cycle and apoptosis regulatory protein-1 peptides suppress the growth of human breast cancer cells in vitro and in vivo
Transactivator of transcription-tagged cell cycle and apoptosis regulatory protein-1 peptides suppress the growth of human breast cancer cells in vitro and in vivo
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DOI：
10.1158/1535-7163.mct-06-0653
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发表时间：
2007-05-01
影响因子：
5.7
通讯作者：
Rishi, Arun K.
中科院分区：
文献类型：
--
作者：
Zhang, Liyue;Levi, Edi;Rishi, Arun K.
在包括乳腺癌在内的人类恶性肿瘤中，表皮生长因子受体蛋白家族的信号调节失调。细胞周期和凋亡调节蛋白-1 （CARP-1）是一种新型的核周磷酸化蛋白，通过表皮生长因子受体调节细胞凋亡信号。CARP-1的表达在人类乳腺癌中减少，并且与人类乳腺癌的等级呈负相关，这可能归因于甲基化的增加。另一方面，CARP-1的表达会干扰人乳腺癌细胞通过基质包被膜侵入，在软琼脂中形成菌落，并在严重联合免疫缺陷（SCID）小鼠中生长为sc肿瘤的能力。为了测试CARP-1是否是人类乳腺癌生长的抑制因子，我们生成了转录反激活因子（TAT）标记的CARP-1肽。用亲和纯化的TAT-CARP-1 1-198、197-454和896-1150肽处理人乳腺癌细胞可抑制人乳腺癌细胞增殖和增加凋亡。相比之下，tat标记的增强绿色荧光蛋白或CARP-1 （1-198(Y192/F)）肽未能抑制细胞增殖或诱导细胞凋亡。除CARP-1 （1-198(Y192/F)）外，CARP-1肽介导的细胞凋亡涉及p38应激激活蛋白激酶和caspase-9的激活。此外，施用TAT-CARP-1(1-198)，而不施用tat标记的增强绿色荧光蛋白或TAT-CARP-1 (1-198(Y192/F))，可抑制SCID小鼠的人乳腺癌细胞源性肿瘤异种移植物的生长。我们得出结论，CARP1是人类乳腺癌生长的抑制因子，其在肿瘤中的表达减少，部分原因是甲基化依赖性沉默。
Deregulated signaling by the epidermal growth factor receptor family of proteins is encountered in human malignancies including breast cancer. Cell cycle and apoptosis-regulatory protein-1 (CARP-1), a novel, perinuclear phosphoprotein, is a regulator of apoptosis signaling by epidermal growth factor receptors. CARP-1 expression is diminished in human breast cancers, and correlates inversely with human breast cancer grades which could be attributed to increased methylation. The expression of CARP-1, on the other hand, interferes with the ability of human breast cancer cells to invade through the matrigel-coated membranes, to form colonies in the soft agar, and to grow as s.c. tumors in severe combined immunodeficiency (SCID) mice. To test whether CARP-1 is a suppressor of human breast cancer growth, we generated transactivator of transcription (TAT)-tagged CARP-1 peptides. Treatment of human breast cancer cells with affinity purified, TAT-CARP-1 1-198, 197-454, and 896-1150 peptides caused inhibition of human breast cancer cell proliferation and elevated apoptosis. In contrast, TAT-tagged enhanced green fluorescent protein or CARP-1 (1-198(Y192/F)) peptide failed to inhibit cell proliferation or induce apoptosis. Apoptosis by CARP-1 peptides, with the exception of CARP-1 (1-198(Y192/F)), involves the activation of p38 stress-activated protein kinase and caspase-9. Moreover, administration of TAT-CARP-1 (1-198), but not TAT-tagged enhanced green fluorescent protein or TAT-CARP-1 (1-198(Y192/F)), inhibits growth of human breast cancer cell-derived tumor xenografts in SCID mice. We conclude that CARP1 is a suppressor of human breast cancer growth, and its expression is diminished in tumors, in part, by methylation-dependent silencing.