Tyrosine receptor kinase B silencing inhibits anoikis‑resistance and improves anticancer efficiency of sorafenib in human renal cancer cells.
Tyrosine receptor kinase B silencing inhibits anoikis‑resistance and improves anticancer efficiency of sorafenib in human renal cancer cells.
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酪氨酸受体激酶 B 沉默可抑制失巢凋亡抵抗并提高索拉非尼在人肾癌细胞中的抗癌效率。
DOI：
10.3892/ijo.2016.3356
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发表时间：
2016
影响因子：
5.2
通讯作者：
Y. Xing
中科院分区：
文献类型：
--
作者：
Peng Zhang;Zengshu Xing;Xuechao Li;Yarong Song;Jun Zhao;Yajun Xiao;Y. Xing
肾细胞癌（renal cell carcinoma，RCC）是成人肾脏最常见的实体肿瘤，分子靶向治疗是治疗转移性RCC的主要方法。索拉非尼作为一种多靶点酪氨酸激酶抑制剂（TKI），显著改善了mRCC患者的临床结局。然而，由于对剂量相关不良反应的不耐受，很少实现完全或长期缓解。因此，有必要探索新的治疗靶分子或提高目前TKI治疗mRCC的疗效。失巢凋亡是一种特殊类型的细胞凋亡，在调节组织内稳态中起着重要的生理作用。失巢凋亡抗性对于包括mRCC在内的各种人类癌症的转移至关重要。然而，mRCC中失巢凋亡抵抗的确切机制仍不清楚。酪氨酸受体激酶B（Trk B）属于神经营养因子受体的Trk家族。以前的研究表明，TrkB的激活或过表达促进了人类癌症的增殖、存活、血管生成、抗失巢凋亡和转移。然而，TrkB与mRCC中失巢凋亡抗性之间的相关性很少报道。本研究的目的是探讨TrkB对mRCC失巢凋亡抵抗和靶向治疗的影响。我们的数据显示，失巢凋亡抗性ACHN细胞表现出对凋亡诱导的凋亡、过度增殖和侵袭的耐受性，并伴有TrkB表达的上调。此外，TrkB基因沉默可通过抑制PI3K/Akt和MEK/ERK通路，诱导凋亡，抑制细胞增殖，延缓索拉非尼的侵袭，并提高索拉非尼对失巢凋亡耐药的ACHN细胞的抗癌效率。我们的数据可能为mRCC提供一种新的潜在治疗策略。
Renal cell carcinoma (RCC) is the most common solid neoplasm of adult kidney, and the major treatment for metastatic RCC (mRCC) is molecular targeted therapy. Sorafenib, as a multi-targeted tyrosine kinase inhibitor (TKI), has significantly improved clinical outcomes of mRCC patients. However, complete or long-term remissions are rarely achieved due to intolerance to dose-related adverse effects. It is therefore, necessary to explore novel target molecules for treatment or to enhance the therapeutic efficiency of present TKI for mRCC treatment. Anoikis is a specific type of apoptosis that plays a vital physiological role in regulating tissue homoeostasis. Anoikis-resistance is of critical importance for metastasis of various human cancers including mRCC. However, the precise mechanisms on anoikis-resistance in mRCC are still unclear. Tyrosine receptor kinase B (TrkB) belongs to the Trk family of neurotrophin receptors. Previous investigations have implied that activation or overexpression of TrkB promoted proliferation, survival, angiogenesis, anoikis-resistance and metastasis in human cancers. Yet, the correlation between TrkB and anoikis-resistance in mRCC has rarely been reported. The aim of the present study was to explore the impact of TrkB on anoikis-resistance and targeted therapy in mRCC. Our data revealed that anoikis-resistant ACHN cells presented with tolerance to detachment-induced apoptosis, excessive proliferation and aggressive invasion, accompanied by upregulation of TrkB expression in contrast to parental cells. Furthermore, TrkB silencing caused apoptosis, inhibited proliferation, retarded invasion as well as improved anticancer efficiency of sorafenib in anoikis-resistant ACHN cells through inactivation of PI3K/Akt and MEK/ERK pathways. Our data may offer a novel potential therapeutic strategy for mRCC.
影响因子：
4
作者：
Wong, Kwok-Kin;Engelman, Jeffrey A.;Cantley, Lewis C.
通讯作者：
Cantley, Lewis C.
影响因子：
9.7
作者：
Jenning, Scott;Tri Pham;Ireland, Shubha Kale;Ruoslahti, Erkki;Biliran, Hector
通讯作者：
Biliran, Hector