RanBP9/TSSC3 complex cooperates to suppress anoikis resistance and metastasis via inhibiting Src-mediated Akt signaling in osteosarcoma.
RanBP9/TSSC3 complex cooperates to suppress anoikis resistance and metastasis via inhibiting Src-mediated Akt signaling in osteosarcoma.
复制标题
RanBP9/TSSC3 复合物通过抑制骨肉瘤中 Src 介导的 Akt 信号传导来协同抑制失巢凋亡抵抗和转移。
DOI：
10.1038/cddis.2016.436
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发表时间：
2016-12-29
影响因子：
9
通讯作者：
Guo QN
中科院分区：
文献类型：
--
作者：
Dai H;Lv YF;Yan GN;Meng G;Zhang X;Guo QN
失巢凋亡抑制是肿瘤细胞转移的先决条件，与化疗耐药和预后不良有关。我们研究了RanBP9 SPRY结构域与TSSC3 PH结构域之间的一种新的相互作用，即RanBP9/TSSC3复合体在骨肉瘤中发挥转录和翻译后调节作用。RanBP9/TSSC3复合体与骨肉瘤细胞的高度耐失巢细胞表型和人骨肉瘤的转移呈负相关。RanBP9与TSSC3协同抑制锚定非依赖性生长，在体外促进失巢凋亡，在体内抑制肺转移。此外，RanBP9/TSSC3复合体介导的失巢抵抗需要RanBP9的SPRY结构域。从机制上讲，RanBP9与TSSC3和Src形成三元复合体作为这种相互作用的支架，抑制了Src和Src依赖的Akt途径的激活，促进了线粒体相关的失巢凋亡。总的来说，新发现的RanBP9/TSSC3复合体通过下调Src依赖的Akt通路加速线粒体相关的失巢凋亡来协同抑制肿瘤转移。本研究为探讨RanBP9和TSSC3双靶向治疗骨肉瘤的意义提供了生物学基础。
Suppression of anoikis is a prerequisite for tumor cell metastasis, which is correlated with chemoresistance and poor prognosis. We characterized a novel interaction between RanBP9 SPRY domain and TSSC3 PH domain by which RanBP9/TSSC3 complex exerts transcription and post-translation regulation in osteosarcoma. RanBP9/TSSC3 complex was inversely correlated with a highly anoikis-resistant phenotype in osteosarcoma cells and metastasis in human osteosarcoma. RanBP9 cooperated with TSSC3 to inhibit anchorage-independent growth and to promote anoikis in vitro and suppress lung metastasis in vivo. Moreover, RanBP9 SPRY domain was required for RanBP9/TSSC3 complex-mediated anoikis resistance. Mechanistically, RanBP9 formed a ternary complex with TSSC3 and Src to scaffold this interaction, which suppressed both Src and Src-dependent Akt pathway activations and facilitated mitochondrial-associated anoikis. Collectively, the newly identified RanBP9/TSSC3 complex cooperatively suppress metastasis via downregulation of Src-dependent Akt pathway to expedite mitochondrial-associated anoikis. This study provides a biological basis for exploring the therapeutic significance of dual targeting of RanBP9 and TSSC3 in osteosarcoma.