Inhibition of uterine sarcoma cell growth through suppression of endogenous tyrosine kinase B signaling.
Inhibition of uterine sarcoma cell growth through suppression of endogenous tyrosine kinase B signaling.
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DOI：
10.1371/journal.pone.0041049
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Terada Y
中科院分区：
文献类型：
--
作者：
Makino K;Kawamura K;Sato W;Kawamura N;Fujimoto T;Terada Y
子宫平滑肌肉瘤是一种侵袭性肿瘤，由于早期诊断困难，通常发现于晚期。由于子宫平滑肌肉瘤对传统的放疗和化疗有抵抗力，因此人们期待开发更有效的药物治疗。采用实时荧光定量RT-PCR和免疫组化技术，我们发现脑源性神经营养因子（BDNF）和神经营养素4/5及其受体酪氨酸激酶B（Trk B）在不同的子宫肉瘤细胞系和子宫平滑肌肉瘤患者的原发肿瘤标本中的表达。我们注意到BDNF的水平比神经营养素-4/5的水平更丰富。此外，TrkB及其配体的表达在多药耐药细胞系和从平滑肌肉瘤患者获得的样品中升高。在培养的子宫肉瘤细胞中，通过用可溶性TrkB胞外域或Trk受体抑制剂K252 a处理来抑制内源性TrkB信号传导，基于细胞活力和增殖、原位末端脱氧核苷酸转移酶介导的2′-脱氧尿苷5′-三磷酸缺口末端标记和caspase-3/7测定，而非活性质膜非渗透性K252 b则无效。相应地，用外源性BDNF处理增加细胞增殖。在体内研究中，在无胸腺裸鼠多药耐药子宫肉瘤细胞肿瘤，我们证明了抑制肿瘤生长的治疗与K252 a，但不是K252 b，反映了细胞增殖减少，细胞凋亡和caspase-3/7活性水平的增加，没有明显的副作用。我们的研究结果表明，TrkB通路的内源性信号有助于子宫肉瘤细胞的生长，抑制这些肿瘤中的TrkB信号可能为子宫肉瘤患者提供一种新的药物治疗。
Uterine leiomyosarcoma is an aggressive tumor typically found at advanced stages due to difficulties with early diagnosis. Because uterine leiomyosarcoma is resistant to conventional radiation and chemotherapy, the development of more potent medical therapeutics is anticipated. Using quantitative real-time RT-PCR and immunostaining, we found the expression of brain-derived neurotrophic factor (BDNF) and neurotropin-4/5, together with their receptor, tyrosine kinase B (TrkB), in different uterine sarcoma cell lines and primary tumor samples from uterine leiomyosarcoma patients. We noted that levels of BDNF were more abundant than those of neurotropin-4/5. Moreover, the expression of TrkB and its ligands was elevated in a multidrug-resistant cell line and samples obtained from patients with leiomyosarcoma. In cultured uterine sarcoma cells, inhibition of endogenous TrkB signaling by treatment with either the soluble TrkB ectodomain or the Trk receptor inhibitor, K252a, suppressed cell proliferation and increased apoptosis based on cell viability and proliferation, in situ terminal deoxynucleotidyl transferase-mediated 2′-deoxyuridine 5′-triphosphate nick end-labeling and caspase-3/7 assays, whereas an inactive plasma membrane nonpermeable K252b was ineffective. Correspondingly, treatment with exogenous BDNF increased cell proliferation. In in vivo studies in athymic nude mice bearing multidrug-resistant uterine sarcoma cell tumors, we demonstrate suppression of tumor growth by treatment with K252a, but not K252b, as reflected by decreased cell proliferation and increased levels of apoptosis and caspase-3/7 activities without obvious side effects. Our findings indicated that endogenous signaling of the TrkB pathway contributed to uterine sarcoma cell growth, and inhibition of TrkB signaling in these tumors could provide a novel medical therapy for patients with uterine sarcomas.
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影响因子：
4.8
作者：
Kawamura, K;Sato, N;Tanaka, T
通讯作者：
Tanaka, T
DOI：
10.1158/1078-0432.ccr-08-1815
发表时间：
2009-05-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Brodeur GM;Minturn JE;Ho R;Simpson AM;Iyer R;Varela CR;Light JE;Kolla V;Evans AE
通讯作者：
Evans AE
影响因子：
45.3
作者：
Eggert, A;Grotzer, MA;Evans, AE
通讯作者：
Evans, AE
DOI：
10.1002/neu.480251107
发表时间：
1994-11-01
期刊：
JOURNAL OF NEUROBIOLOGY
影响因子：
--
作者：
BARBACID, M
通讯作者：
BARBACID, M
DOI：
10.1016/0002-9378(90)91298-q
发表时间：
1990-04-01
影响因子：
9.8
作者：
LEIBSOHN, S;DABLAING, G;SCHLAERTH, JB
通讯作者：
SCHLAERTH, JB