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RanBP9/TSSC3复合物通过抑制骨肉瘤中Src介导的Akt信号传导协同抑制失巢凋亡抗性和转移。

RanBP9/TSSC3 complex cooperates to suppress anoikis resistance and metastasis via inhibiting Src-mediated Akt signaling in osteosarcoma.

作者信息

Dai Huanzi, Lv Yang-Fan, Yan Guang-Ning, Meng Gang, Zhang Xi, Guo Qiao-Nan

机构信息

Department of Pathology, Xinqiao Hospital, The Third Military Medical University, Chongqing, People's Republic of China.

Department of Nephrology, Daping Hospital, Third Military Medical University, Chongqing, People's Republic of China.

出版信息

Cell Death Dis. 2016 Dec 29;7(12):e2572. doi: 10.1038/cddis.2016.436.

DOI:10.1038/cddis.2016.436
PMID:28032865
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5261021/
Abstract

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.

摘要

失巢凋亡的抑制是肿瘤细胞转移的前提条件，这与化疗耐药性和不良预后相关。我们鉴定了RanBP9 SPRY结构域与TSSC3 PH结构域之间的一种新型相互作用，通过这种相互作用，RanBP9/TSSC3复合物在骨肉瘤中发挥转录和翻译后调控作用。RanBP9/TSSC3复合物与骨肉瘤细胞中高度抗失巢凋亡的表型以及人类骨肉瘤的转移呈负相关。RanBP9与TSSC3协同作用，在体外抑制非锚定依赖性生长并促进失巢凋亡，在体内抑制肺转移。此外，RanBP9 SPRY结构域是RanBP9/TSSC3复合物介导的失巢凋亡抗性所必需的。从机制上讲，RanBP9与TSSC3和Src形成三元复合物以维持这种相互作用，这抑制了Src和Src依赖性Akt途径的激活，并促进了线粒体相关的失巢凋亡。总的来说，新鉴定的RanBP9/TSSC3复合物通过下调Src依赖性Akt途径协同抑制转移，以加速线粒体相关的失巢凋亡。这项研究为探索RanBP9和TSSC3双重靶向治疗骨肉瘤的意义提供了生物学基础。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ef51/5261021/8db19a49882e/cddis2016436f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ef51/5261021/c79cd6807d4d/cddis2016436f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ef51/5261021/4e286a149ecf/cddis2016436f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ef51/5261021/9481b07f8dad/cddis2016436f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ef51/5261021/7eb679d5ab71/cddis2016436f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ef51/5261021/55d4df7181cc/cddis2016436f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ef51/5261021/8db19a49882e/cddis2016436f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ef51/5261021/c79cd6807d4d/cddis2016436f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ef51/5261021/4e286a149ecf/cddis2016436f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ef51/5261021/9481b07f8dad/cddis2016436f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ef51/5261021/7eb679d5ab71/cddis2016436f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ef51/5261021/55d4df7181cc/cddis2016436f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ef51/5261021/8db19a49882e/cddis2016436f6.jpg

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