Artemin, a Member of the Glial Cell Line-derived Neurotrophic Factor Family of Ligands, Is HER2-regulated and Mediates Acquired Trastuzumab Resistance by Promoting Cancer Stem Cell-like Behavior in Mammary Carcinoma Cells

被引：30

作者：

Ding, Keshuo ^{[1
,2
]}

Banerjee, Arindam ^{[5
,6
]}

Tan, Sheng ^{[1
,2
]}

Zhao, JunSong ^{[1
,2
]}

Zhuang, Qian ^{[1
,2
]}

Li, Rui ^{[1
,2
]}

Qian, Pengxu ^{[1
,2
]}

Liu, Suling ^{[1
,2
]}

Wu, Zheng-Sheng ^{[1
,2
,3
,4
]}

Lobie, Peter E. ^{[5
,6
,7
]}

Zhu, Tao ^{[1
,2
]}

机构：

[1] Univ Sci & Technol China, Hefei Natl Lab Phys Sci Microscale, Hefei 230027, Anhui, Peoples R China

[2] Univ Sci & Technol China, Sch Life Sci, Hefei 230027, Anhui, Peoples R China

[3] Anhui Med Univ, Dept Pathol, Hefei 230032, Anhui, Peoples R China

[4] Fudan Univ, Shanghai Med Coll, Dept Pathol, Shanghai 200433, Peoples R China

[5] Natl Univ Singapore, Canc Sci Inst Singapore, Singapore 117599, Singapore

[6] Natl Univ Singapore, Dept Pharmacol, Singapore 117599, Singapore

[7] Natl Univ Hlth Syst, Natl Canc Inst Singapore, Singapore 119074, Singapore

来源：

JOURNAL OF BIOLOGICAL CHEMISTRY | 2014年 / 289卷 / 23期

基金：

中国国家自然科学基金; 新加坡国家研究基金会;

关键词：

HUMAN-BREAST-CANCER; PROGNOSTIC-SIGNIFICANCE; BCL-2; EXPRESSION; GROWTH; RECEPTOR; ACTIVATION; HERCEPTIN; GDNF; HER2; NEU;

D O I：

10.1074/jbc.M113.529552

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

Previous studies have demonstrated that Artemin (ARTN) functions as a cancer stem cell (CSC) and metastatic factor in mammary carcinoma. Herein, we report that ARTN mediates acquired resistance to trastuzumab in HER2-positive mammary carcinoma cells. Ligands that increase HER2 activity increased ARTN expression in HER2-positive mammary carcinoma cells, whereas trastuzumab inhibited ARTN expression. Forced expression of ARTN decreased the sensitivity of HER2-positive mammary carcinoma cells to trastuzumab both in vitro and in vivo. Conversely, siRNA-mediated depletion of ARTN enhanced trastuzumab efficacy. Cells with acquired resistance to trastuzumab exhibited increased ARTN expression, the depletion of which restored trastuzumab sensitivity. Trastuzumab resistance produced an increased CSC population concomitant with enhanced mammospheric growth. ARTN mediated the enhancement of the CSC population by increased BCL-2 expression, and the CSC population in trastuzumab-resistant cells was abrogated upon inhibition of BCL-2. Hence, we conclude that ARTN is one mediator of acquired resistance to trastuzumab in HER2-positive mammary carcinoma cells.

引用

页码：16057 / 16071

页数：15

共 52 条

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