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

Dai, Huanzi; Lv, Yang‐Fan; Yan, Guangning; Ma, Gang; Zhang, Xi; Guo, Qiao‐Nan

doi:10.1038/cddis.2016.436

Cited by 30 publications

(42 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In particular, it may favor vesicle trafficking such as the gephyrin-mediated transport of GABA receptors to the surface membrane helped by dynactin, Kif5, and Hap1 23 , 24 and nucleocytoplasmic shuttling mediated by Ran-binding proteins (RANBP) 25 . PI3K activation may also promote the activation of Src-integrin complex which in turn confers anti-anoikis properties 26 , 27 . In particular, the Src-integrin complex together with ranbp9 may favour endocytosis, which is anti-amyloidogenic 28 .…”

Section: Resultsmentioning

confidence: 99%

Neuroprotective Drug for Nerve Trauma Revealed Using Artificial Intelligence

Romeo-Guitart

Forés

Herrando-Grabulosa

et al. 2018

Sci Rep

View full text Add to dashboard Cite

Here we used a systems biology approach and artificial intelligence to identify a neuroprotective agent for the treatment of peripheral nerve root avulsion. Based on accumulated knowledge of the neurodegenerative and neuroprotective processes that occur in motoneurons after root avulsion, we built up protein networks and converted them into mathematical models. Unbiased proteomic data from our preclinical models were used for machine learning algorithms and for restrictions to be imposed on mathematical solutions. Solutions allowed us to identify combinations of repurposed drugs as potential neuroprotective agents and we validated them in our preclinical models. The best one, NeuroHeal, neuroprotected motoneurons, exerted anti-inflammatory properties and promoted functional locomotor recovery. NeuroHeal endorsed the activation of Sirtuin 1, which was essential for its neuroprotective effect. These results support the value of network-centric approaches for drug discovery and demonstrate the efficacy of NeuroHeal as adjuvant treatment with surgical repair for nervous system trauma.

show abstract

Section: Resultsmentioning

confidence: 99%

Neuroprotective Drug for Nerve Trauma Revealed Using Artificial Intelligence

Romeo-Guitart

Forés

Herrando-Grabulosa

et al. 2018

Sci Rep

View full text Add to dashboard Cite

show abstract

“…The proliferation of osteosarcoma cells was inhibited by TIMP3 overexpression, whereas TIMP3 knockdown had an antagonistic effect. Akt signaling has been reported to play essential roles in the progression of many tumors, including osteosarcoma ( Keremu et al, 2017 ; Liu et al, 2017 ; Ma et al, 2017 ), and the PI3K/Akt pathway participates in almost all malignant processes, including tumorigenesis, cancer cell proliferation, metastasis, angiogenesis, and chemoresistance ( Yuan and Cantley, 2008 ; Berlanga et al, 2016 ; Dai et al, 2016 ; Davaadelger et al, 2016 ). Our results showed that the p-Akt level correlated negatively with TIMP-3 expression.…”

Section: Discussionmentioning

confidence: 99%

TIMP3 Overexpression Improves the Sensitivity of Osteosarcoma to Cisplatin by Reducing IL-6 Production

Han

Liu

et al. 2018

Front. Genet.

View full text Add to dashboard Cite

Osteosarcoma is the most common bone cancer in children and adolescents. Tissue inhibitors of metalloproteinases (TIMPs)-3 inhibit matrix metalloproteinases to limit extracellular matrix degradation. Cisplatin is a widely used chemotherapeutic drug used to cure osteosarcoma. Interleukin (IL)-6 and TIMP3 play important roles in the drug resistance of osteosarcoma; however, their relationship in this process remains unclear. This study aimed to explore the role of TIMP3 in the cisplatin sensitivity of osteosarcoma and its underlying molecular mechanisms in vitro and in vivo. We compared TIMP3 expression levels between patients with cisplatin-sensitive and -insensitive osteosarcoma. TIMP3 was overexpressed or knocked down in the Saos2-lung cell line, which is a Saos2 subtype isolated from pulmonary metastases that has higher cisplatin chemoresistance than Saos2 cells. IL-6 expression, cell proliferation, sensitivity to cisplatin, migration, and invasion after TIMP3 overexpression or knockdown were determined. The same experiments were performed using MG63 and U2OS cells. Subsequently, luciferase-labeled Saos2-lung cells overexpressing TIMP3 were injected into the tibiae of nude mice treated with cisplatin. The results showed that IL-6 inhibited TIMP3 expression in Saos2 and Saos2-lung cells via signal transducer and activator of transcription 3 (STAT3) activation. STAT3 knockdown reversed the effect of IL-6. The expression of TIMP3 was higher in patients with cisplatin-sensitive osteosarcoma than in those with insensitive osteosarcoma. IL-6 expression was downregulated upon TIMP3 overexpression, and upregulated by TIMP3 knockdown. TIMP3 overexpression suppressed cell proliferation and enhanced cisplatin sensitivity by activating apoptosis-related signal pathways and inhibiting IL-6 expression in vitro and in vivo. In conclusion, cisplatin sensitivity correlated positively with TIMP3 expression, which is regulated by the IL-6/TIMP3/caspase pathway. The TIMP3 pathway could represent a target for new therapies to treat osteosarcoma.

show abstract

“…Src was the first oncogene to be discovered with tyrosine kinase activity to activate the Akt pathway [ 45 ], and leads to anchorage-independent growth and anoikis resistance [ 46 ]. Studies from our lab indicate that TSSC3 binds to Src with Ranbp9 and prevents its phosphorylation, resulting in apoptosis [ 47 ], which prompted us to hypothesize that TSSC3 inhibition of Nanog expression was likely mediated by Src inactivation. We then demonstrated that overexpression of TSSC3 inactivates the Src/Akt pathway, and Src inactivation in OS cells inhibits Nanog expression.…”

Section: Discussionmentioning

confidence: 99%

TSSC3 represses self-renewal of osteosarcoma stem cells and Nanog expression by inhibiting the Src/Akt pathway

et al. 2017

Self Cite

View full text Add to dashboard Cite

Osteosarcoma is the most common type of bone cancer, and the second leading cause of cancer-related death in children and young adults. Osteosarcoma stem cells are essential for osteosarcoma initiation, metastasis, chemoresistance and recurrence. In the present study, we report that: 1) higher TSSC3 expression indicates a better prognosis for osteosarcoma patients, and; 2) overexpression of TSSC3 significantly decreases sphere-forming capacity, tumor initiation, stemness-related surface markers and Nanog expression in osteosarcoma cells. We also discovered that higher Nanog expression correlates to a worse prognosis for osteosarcoma patients, and overexpression of Nanog increases the stem-related phenotype in osteosarcoma cells. Knockdown of Nanog suppresses these phenotypes. Inhibition of Nanog expression and self-renewal of osteosarcoma cells by TSSC3 overexpression appears to be mediated through inactivation of the Src/Akt pathway. In the clinical setting, expression of TSSC3, p-Src and Nanog is associated with recurrence, metastasis and surgical intervention. Lower TSSC3 expression, higher Nanog expression or higher p-Src expression indicate a poor prognosis for osteosarcoma patients. Overall, our study demonstrates that TSSC3 inhibits the stem-like phenotype and Nanog expression by inactivation of the Src/Akt pathway; this emphasizes the importance of Nanog in osteosarcoma stem cells.

show abstract

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

Cited by 30 publications

References 48 publications

Neuroprotective Drug for Nerve Trauma Revealed Using Artificial Intelligence

Neuroprotective Drug for Nerve Trauma Revealed Using Artificial Intelligence

TIMP3 Overexpression Improves the Sensitivity of Osteosarcoma to Cisplatin by Reducing IL-6 Production

TSSC3 represses self-renewal of osteosarcoma stem cells and Nanog expression by inhibiting the Src/Akt pathway

Contact Info

Product

Resources

About