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

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.
Mesh Terms:
Adaptor Proteins, Signal Transducing, Adolescent, Adult, Animals, Anoikis, Cell Line, Tumor, Cell Proliferation, Child, Cytoskeletal Proteins, Down-Regulation, Female, Humans, Lung Neoplasms, Male, Mice, SCID, Mitochondria, Models, Biological, Nuclear Proteins, Osteosarcoma, Phenotype, Protein Binding, Protein Domains, Protein Processing, Post-Translational, Proto-Oncogene Proteins c-akt, Signal Transduction, Transcription, Genetic, Young Adult, src-Family Kinases
Cell Death Dis
Date: Dec. 29, 2015
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