The ErbB3-binding protein EBP1 modulates lapatinib sensitivity in prostate cancer cells.
The ErbB3-binding protein EBP1 modulates lapatinib sensitivity in prostate cancer cells.
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DOI：
10.1007/s11010-015-2409-z
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发表时间：
2015-07
影响因子：
4.3
通讯作者：
Hamburger, Anne W.
中科院分区：
文献类型：
--
作者：
Awasthi, Smita;Ezelle, Heather;Hassel, Bret A.;Hamburger, Anne W.
尽管ErbB受体与前列腺癌进展有关，但ErbB靶向药物尚未被证明对前列腺癌治疗有效。ErbB 3结合蛋白EBP 1影响ErbB 2和雄激素受体信号传导，这是ErbB靶向治疗反应的两个组成部分。因此，我们研究了EBP 1表达对ErbB 1/2酪氨酸激酶抑制剂拉帕替尼反应的影响。我们发现内源性EBP 1水平与前列腺癌细胞系中拉帕替尼敏感性呈负相关。然后我们过度表达或抑制EBP 1的表达。在含雄激素的培养基中，沉默EBP 1表达增加拉帕替尼敏感性，EBP 1过表达增加耐药性。雄激素耗竭导致雄激素依赖性EBP 1表达细胞对拉帕替尼的敏感性增加，但不影响激素抵抗细胞对拉帕替尼的敏感性。然而，EBP 1沉默的细胞仍然比EBP 1表达细胞在雄激素的情况下对拉帕替尼更敏感。EBP 1沉默后拉帕替尼敏感性的增加与ErbB 2水平的增加相关。此外，拉帕替尼治疗增加了表达低水平EBP 1的敏感细胞中的ErbB 2水平，但降低了表达耐药EBP 1的细胞中的ErbB 2水平。相反，ErbB 3和磷酸化ErbB 3水平不受EBP 1水平变化或拉帕替尼治疗的影响。ErbB 3/4配体heregulin的产生在EBP 1沉默的细胞中增加。EBP 1诱导的AR水平变化与拉帕替尼敏感性变化无关。这些研究表明，EBP 1激活ErbB 2信号通路的能力导致拉帕替尼敏感性增加。
Although ErbB receptors have been implicated in prostate cancer progression, ErbB-directed drugs have not proven effective for prostate cancer treatment. The ErbB3-binding protein EBP1 affects both ErbB2 and androgen receptor signaling, two components of the response to ErbB-targeted therapies. We therefore examined the effects of EBP1 expression on the response to the ErbB1/2 tyrosine kinase inhibitor lapatinib. We found a negative correlation between endogenous EBP1 levels and lapatinib sensitivity in prostate cancer cell lines. We then overexpressed or inhibited expression of EBP1. Silencing EBP1 expression increased lapatinib sensitivity and overexpression of EBP1 increased resistance in androgen-containing media. Androgen depletion resulted in an increased sensitivity of androgen-dependent EBP1 expressing cells to lapatinib, but did not affect the lapatinib sensitivity of hormone resistant cells. However, EBP1 silenced cells were still more sensitive to lapatinib than EBP1-expressing cells in the absence of androgens. The increase in sensitivity to lapatinib following EBP1 silencing was associated with increased ErbB2 levels. In addition, lapatinib treatment increased ErbB2 levels in sensitive cells that express low levels of EBP1, but decreased ErbB2 levels in resistant EBP1-expressing cells. In contrast, ErbB3 and phospho ErbB3 levels were not affected by either changes in EBP1 levels or lapatinib treatment. The production of the ErbB3/4 ligand heregulin was increased in EBP1-silenced cells. EBP1-induced changes in AR levels were not associated with changes in lapatinib sensitivity. These studies suggest that the ability of EBP1 to activate ErbB2 signaling pathways results in increased lapatinib sensitivity.
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DOI：
10.1016/j.bbrc.2006.03.205
发表时间：
2006-06-09
影响因子：
3.1
作者：
Squatrito, M;Mancino, M;Draetta, GF
通讯作者：
Draetta, GF
影响因子：
2.8
作者：
Tal-Or, P;Di-Segni, A;Pinkas-Kramarski, R
通讯作者：
Pinkas-Kramarski, R
影响因子：
11.2
作者：
Berger, Raanan;Lin, Douglas I.;Loda, Massimo
通讯作者：
Loda, Massimo
影响因子：
11.2
作者：
Mukhopadhyay NK;Kim J;Cinar B;Ramachandran A;Hager MH;Di Vizio D;Adam RM;Rubin MA;Raychaudhuri P;De Benedetti A;Freeman MR
通讯作者：
Freeman MR
影响因子：
50.3
作者：
Agus, DB;Akita, RW;Sliwkowski, MX
通讯作者：
Sliwkowski, MX