Overexpression of RACK1 Promotes Metastasis by Enhancing Epithelial-Mesenchymal Transition and Predicts Poor Prognosis in Human Glioma

Lv, Qiao‐Li; Huang, Yuan-Tao; Wang, Guihua; Liu, Yanling; Huang, Jin; Qu, Qiang; Sun, Bao; Hu, Lei; Cheng, Lin; Chen, Shuhui; Zhou, Hong‐Hao

doi:10.3390/ijerph13101021

Cited by 26 publications

(23 citation statements)

References 36 publications

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“…Moreover, several studies have shown that pY23-Anxa2 promotes cancer cell invasion and metastasis through enhancing epithelial-mesenchymal transition (EMT) [46,60,70]. Likewise, Rack1 has also been reported to regulate EMT and contribute cancer metastasis [71,72]. Drug-resistant cells are always associated with EMT phenotype [73][74][75].…”

Section: Discussionmentioning

confidence: 99%

Rack1 mediates tyrosine phosphorylation of Anxa2 by Src and promotes invasion and metastasis in drug-resistant breast cancer cells

Fan

et al. 2019

Breast Cancer Res

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Background: Acquirement of resistance is always associated with a highly aggressive phenotype of tumor cells. Recent studies have revealed that Annexin A2 (Anxa2) is a key protein that links drug resistance and cancer metastasis. A high level of Anxa2 in cancer tissues is correlated to a highly aggressive phenotype. Increased Anxa2 expression appears to be specific in many drug-resistant cancer cells. The functional activity of Anxa2 is regulated by tyrosine phosphorylation at the Tyr23 site. Nevertheless, the accurate molecular mechanisms underlying the regulation of Anxa2 tyrosine phosphorylation and whether phosphorylation is necessary for the enhanced invasive phenotype of drug-resistant cells remain unknown. Methods: Small interfering RNAs, small molecule inhibitors, overexpression, loss of function or gain of function, rescue experiments, Western blot, wound healing assays, transwell assays, and in vivo metastasis mice models were used to investigate the functional effects of Rack1 and Src on the tyrosine phosphorylation of Anxa2 and the invasion and metastatic potential of drug-resistant breast cancer cells. The interaction among Rack1, Src, and Anxa2 in drug-resistant cells was verified by co-immunoprecipitation assay. Results: We demonstrated that Anxa2 Tyr23 phosphorylation is necessary for multidrug-resistant breast cancer invasion and metastasis. Rack1 is required for the invasive and metastatic potential of drug-resistant breast cancer cells through modulating Anxa2 phosphorylation. We provided evidence that Rack1 acts as a signal hub and mediates the interaction between Src and Anxa2, thereby facilitating Anxa2 phosphorylation by Src kinase. Conclusions: Our findings suggest a convergence point role of Rack1/Src/Anxa2 complex in the crosstalk between drug resistance and cancer aggressiveness. The interaction between Anxa2 and Rack1/Src is responsible for the association between drug resistance and invasive/metastatic potential in breast cancer cells. Thus, our findings provide novel insights on the mechanism underlying the functional linkage between drug resistance and cancer aggressiveness.

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Section: Discussionmentioning

confidence: 99%

Rack1 mediates tyrosine phosphorylation of Anxa2 by Src and promotes invasion and metastasis in drug-resistant breast cancer cells

Fan

et al. 2019

Breast Cancer Res

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“…In fact both in vitro and in vivo studies have shown that RACK 1 promotes the proliferation, invasion and metastasis of breast cancer (57) and remains one of the independent predictors for poor clinical outcome in breast cancer (58). Perhaps RACK1 was not only associated with breast cancer malignancy, but its overexpression is implicated in the growth and metastasis of several other cancer types such as lung cancer, gliomas, colon cancer, prostate cancer, liver cancer, epithelial ovarian cancer and squamous cell carcinoma of the esophagus (59). Finally, the top ve proteins found to be upregulated in our analysis included Filamin A.…”

Section: Discussionmentioning

confidence: 99%

Proteomic Analysis of CRISPR Cas 9 Mediated Mdig Deletion in Triple Negative Breast Cancer Cells

Thakur

Zhang

Carruthers

et al. 2020

Preprint

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BackgroundWe have identified an environmentally inducible gene, mdig that predicted the overall survival in breast cancer patients. We showed that mdig regulated breast cancer cell growth, motility and invasion partially through DNA and histone methylation. However, we have lacked a comprehensive analysis of the proteomic profile of mdig in triple negative breast cancer cells. MethodsWe applied mass spectrometry to acquire global proteomic and post translational modification analysis for triple negative breast cancer cells MDA-MB-231 that had mdig deleted via CRISPR Cas 9 gene editing. Using label-free bottom up quantitative proteomics, we compared wildtype control (WT) and mdig knockout (KO) MDA-MB-231 cells and identified the proteins and pathways that are significantly altered with mdig deletion. The Ingenuity Pathway Analysis (IPA) platform was further used to explore the signaling pathway networks incorporating differentially expressed proteins. Results904 differentially expressed (p < 0.005) proteins were identified in MDA-MB-231 cells that had mdig deletion. Approximately 30 pathways and networks linked to the pathogenicity of breast cancer and populated by the differentially expressed proteins were either activated or inhibited. IPA established that the differentially expressed proteins have relevant biological actions in cell growth, motility and malignancy. This analysis provides a rich source of potential candidate therapeutic targets with potential prognostic significance in triple negative breast cancer. Data are available via ProteomeXchange with identifier PXD016688.Conclusions These data provide the first insight into protein expression patterns in breast cancer associated with a complete disruption of the mdig gene. Differentially expressed proteins between WT and KO MDA-MB-231 triple negative breast cancer cells provide substantial information regarding key proteins, biological process and pathways that are modulated by mdig and contribute to breast cancer tumorigenicity and invasiveness. Mdig modulated signaling pathways and hub molecules provide novel targets for the development of treatment strategies and breast cancer therapies.

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“…Actually, GNB2L1 has been reported to regulate EMT in different kinds of cancers including esophageal squamous cell carcinoma and Glioma [ 22 , 23 ]. Intriguingly, although previous studies revealed that GNB2L1 led to the protein level change of different EMT-related proteins in WB and IHC analysis, they didn’t observe similar changes in mRNA levels of these proteins [ 22 , 23 ]. Consistent with their results, we also failed to detect the changes of mRNA levels resulted from GNB2L1 in the chemoresistance of gastric cancer.…”

Section: Discussionmentioning

confidence: 99%

GNB2L1 and its O-GlcNAcylation regulates metastasis via modulating epithelial-mesenchymal transition in the chemoresistance of gastric cancer

et al. 2017

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GNB2L1 and its O-GlcNAcylation has been reported to play roles in gastric cancer metastasis. However, the roles of GNB2L1 in chemoresistance of gastric cancer has never been determined. In the present study, we found that GNB2L1 was downregulated in chemoresistant patients of gastric cancer, and observed the decrease of GNB2L1 in protein levels instead of mRNA levels in different chemoresistant gastric cancer cell lines. Further we proved that this downregulation of GNB2L1 was resulted from its elevated O-GlcNAcylation catalyzed by OGT in both cell lines and patients. Next, we investigate the function of GNB2L1 and its O-GlcNAcylation on gastric cancer metastasis during chemoresistance, and confirmed Ser124 as the major O-GlcNAcylation site on GNB2L1 that regulated its function on metastasis. Furthermore, our data demonstrated that GNB2L1 modulated EMT via regulating the translation of EMT-related proteins in the process of chemoresistance. In summary, this study indicated that GNB2L1 and its O-GlcNAcylation regulated metastasis via modulating the translation of EMT-related proteins in the chemoresistance of gastric cancer.

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Overexpression of RACK1 Promotes Metastasis by Enhancing Epithelial-Mesenchymal Transition and Predicts Poor Prognosis in Human Glioma

Cited by 26 publications

References 36 publications

Rack1 mediates tyrosine phosphorylation of Anxa2 by Src and promotes invasion and metastasis in drug-resistant breast cancer cells

Rack1 mediates tyrosine phosphorylation of Anxa2 by Src and promotes invasion and metastasis in drug-resistant breast cancer cells

Proteomic Analysis of CRISPR Cas 9 Mediated Mdig Deletion in Triple Negative Breast Cancer Cells

GNB2L1 and its O-GlcNAcylation regulates metastasis via modulating epithelial-mesenchymal transition in the chemoresistance of gastric cancer

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