SEMA3C drives cancer growth by transactivating multiple receptor tyrosine kinases via Plexin B1.

SEMA3C 通过神经丛蛋白 B1 反式激活多种受体酪氨酸激酶来驱动癌症生长。

• 影响指数: 14.26
• 发表时间: 02 2018
• 来源期刊: EMBO Mol Med
• DOI: 10.15252/emmm.201707689
• PMID: 29348142
• 文章类型: Journal Article
• 中科院分区: Q1
• 方向: 医学
• 作者列表: Peacock JW,Takeuchi A,Hayashi N,Liu L,Tam KJ,Al Nakouzi N,Khazamipour N,Tombe T,Dejima T,Lee KC,Shiota M,Thaper D,Lee WC,Hui DH,Kuruma H,Ivanova L,Yenki P,Jiao IZ,Khosravi S,Mui AL,Fazli L,Zoubeidi A,Daugaard M,Gleave ME,Ong CJ

关键词: Plexin B1; Semaphorin 3C; apoptosis; prostate cancer; receptor tyrosine kinase

Mesh: Animals; Cell Proliferation; Humans; Male; Mice; Nerve Tissue Proteins / metabolism; Prostatic Neoplasms, Castration-Resistant / metabolism pathology; Receptor Protein-Tyrosine Kinases / metabolism; Receptors, Cell Surface / metabolism; Semaphorins / antagonists & inhibitors metabolism; Signal Transduction; Xenograft Model Antitumor Assays

Abstract

Growth factor receptor tyrosine kinase (RTK) pathway activation is a key mechanism for mediating cancer growth, survival, and treatment resistance. Cognate ligands play crucial roles in autocrine or paracrine stimulation of these RTK pathways. Here, we show SEMA3C drives activation of multiple RTKs including EGFR, ErbB2, and MET in a cognate ligand-independent manner via Plexin B1. SEMA3C expression levels increase in castration-resistant prostate cancer (CRPC), where it functions to promote cancer cell growth and resistance to androgen receptor pathway inhibition. SEMA3C inhibition delays CRPC and enzalutamide-resistant progression. Plexin B1 sema domain-containing:Fc fusion proteins suppress RTK signaling and cell growth and inhibit CRPC progression of LNCaP xenografts post-castration in vivo SEMA3C inhibition represents a novel therapeutic strategy for treatment of advanced prostate cancer.

摘要

生长因子受体酪氨酸激酶(RTK)通路激活是介导肿瘤生长的关键机制,生存,和治疗阻力。同源配体在这些RTK途径的自分泌或旁分泌刺激中起关键作用。这里,我们显示SEMA3C驱动包括EGFR在内的多种RTK的激活，ErbB2和MET以同源配体非依赖性方式通过神经丛蛋白B1。SEMA3C表达水平在去势抵抗前列腺癌（CRPC）中增加，它的作用是促进癌细胞生长和对雄激素受体途径抑制的抗性。SEMA3C抑制延迟CRPC和恩杂鲁胺耐药的进展。含有神经丛蛋白B1sema结构域的Fc融合蛋白抑制RTK信号传导和细胞生长并抑制体内去势后LNCaP异种移植物的CRPC进展SEMA3C抑制代表了用于治疗晚期前列腺癌的新型治疗策略。