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• W4311115652 abstract "The stimulator of interferon genes (STING) pathway is vital for immune defense against pathogen invasion and cancer. Although ample evidence substantiates that the STING signaling pathway plays an essential role in various cancers via cytokines, no comprehensive investigation of secretory proteins regulated by the STING pathway has been conducted hitherto. Herein, we identify 24 secretory proteins significantly regulated by the STING signaling pathway through quantitative proteomics. Mechanistic analyses reveal that STING activation inhibits the translation of urokinase-type plasminogen activator (PLAU) via the STING-PERK-eIF2α signaling axis. PLAU is highly expressed in a variety of cancers and promotes the migration and invasion of cancer cells. Notably, the activation of STING inhibits cancer cell migration and invasion by suppressing PLAU. Collectively, these results provide novel insights into the anticancer mechanism of the STING pathway, offering a theoretical basis for precision therapy for this patient population. The stimulator of interferon genes (STING) pathway is vital for immune defense against pathogen invasion and cancer. Although ample evidence substantiates that the STING signaling pathway plays an essential role in various cancers via cytokines, no comprehensive investigation of secretory proteins regulated by the STING pathway has been conducted hitherto. Herein, we identify 24 secretory proteins significantly regulated by the STING signaling pathway through quantitative proteomics. Mechanistic analyses reveal that STING activation inhibits the translation of urokinase-type plasminogen activator (PLAU) via the STING-PERK-eIF2α signaling axis. PLAU is highly expressed in a variety of cancers and promotes the migration and invasion of cancer cells. Notably, the activation of STING inhibits cancer cell migration and invasion by suppressing PLAU. Collectively, these results provide novel insights into the anticancer mechanism of the STING pathway, offering a theoretical basis for precision therapy for this patient population. The stimulator of interferon genes (STING) pathway is an important innate immune signaling pathway that defends against pathogens (1Ishikawa H. Barber G.N. STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling.Nature. 2008; 455: 674-678Crossref PubMed Scopus (2048) Google Scholar). When pathogens invade cells and release DNA, cyclic GMP-AMP synthase (cGAS), a cytoplasmic dsDNA receptor, can sense this aberrantly present dsDNA and then forms a dimer and undergoes a conformational change in its active region upon binding with DNA and synthesizes the second messenger cGAMP from AMP and GMP (2Li X. Shu C. Yi G. Chaton C.T. Shelton C.L. Diao J. et al.Cyclic GMP-AMP synthase is activated by double-stranded DNA-induced oligomerization.Immunity. 2013; 39: 1019-1031Abstract Full Text Full Text PDF PubMed Scopus (355) Google Scholar). The binding of cGAMP to STING that locates in the endoplasmic reticulum causes a conformational change in the transmembrane domain of STING, which leads to the formation of the STING tetramer and higher order oligomers through side-by-side packing (3Shang G. Zhang C. Chen Z.J. Bai X. Zhang X. Cryo-EM structures of STING reveal its mechanism of activation by cyclic GMP–AMP.Nature. 2019; 567: 389-393Crossref PubMed Scopus (266) Google Scholar). Then, the endoplasmic reticulum–Golgi intermediate compartment containing STING oligomers transports STING from the endoplasmic reticulum to post-Golgi vesicles where STING recruits the tank-binding kinase 1 (TBK1) and is phosphorylated by TBK1 (4Zhang C. Shang G. Gui X. Zhang X. Bai X. Chen Z.J. Structural basis of STING binding with and phosphorylation by TBK1.Nature. 2019; 567: 394-398Crossref PubMed Scopus (361) Google Scholar, 5Gui X. Yang H. Li T. Tan X. Shi P. Li M. et al.Autophagy induction via STING trafficking is a primordial function of the cGAS pathway.Nature. 2019; 567: 262-266Crossref PubMed Scopus (473) Google Scholar). The phosphorylated C-terminal tail of STING recruits the nuclear transcription factor interferon regulatory factor 3 (IRF3), which is phosphorylated by TBK1 and forms dimer to translocate into the nucleus, turns on the transcription of type one interferons, interferon-stimulated genes, and chemokines, triggering immune clearance and immune defense (6Chen W. Li S. Yu H. Liu X. Huang L. Wang Q. et al.ER adaptor SCAP translocates and recruits IRF3 to perinuclear microsome induced by cytosolic microbial DNAs.PLoS Pathog. 2016; 12e1005462Crossref Scopus (42) Google Scholar, 7Zhao B. Du F. Xu P. Shu C. Sankaran B. Bell S.L. et al.A conserved PLPLRT/SD motif of STING mediates the recruitment and activation of TBK1.Nature. 2019; 569: 718-722Crossref PubMed Scopus (149) Google Scholar). It is well established that the STING pathway plays an essential role in tumor development and progression. Spontaneous tumor antigen-specific T-cell priming is dependent on host type I IFN production, via a mechanism that involves the promotion of crosspresentation by CD8α+ DCs (8Diamond M.S. Kinder M. Matsushita H. Mashayekhi M. Dunn G.P. Archambault J.M. et al.Type I interferon is selectively required by dendritic cells for immune rejection of tumors.J. Exp. Med. 2011; 208: 1989-2003Crossref PubMed Scopus (731) Google Scholar, 9Fuertes M.B. Kacha A.K. Kline J. Woo S.-R. Kranz D.M. Murphy K.M. et al.Host type I IFN signals are required for antitumor CD8+ T cell responses through CD8{alpha}+ dendritic cells.J. Exp. Med. 2011; 208: 2005-2016Crossref PubMed Scopus (807) Google Scholar). Seng-Ryong Woo et al. found that spontaneous CD8+ T-cell priming against tumors is defective in mice lacking STING, but not other innate signaling pathways, suggesting that the major mechanism for innate immune sensing of cancer is via the cGAS-STING pathway (10Woo S.-R. Fuertes M.B. Corrales L. Spranger S. Furdyna M.J. Leung M.Y.K. et al.STING-dependent cytosolic DNA sensing mediates innate immune recognition of immunogenic tumors.Immunity. 2014; 41: 830-842Abstract Full Text Full Text PDF PubMed Scopus (1039) Google Scholar). The STING signaling pathway is necessary for radiotherapy to exert an antitumor effect and serves as a bridge between innate and adaptive immune responses. Studies have shown that the anticancer effects of radiotherapy and targeted therapy depend on the normal expression of STING. Meanwhile, in STING KO mice, CD8+ T cells that should be activated by tumor-associated antigens cannot be activated normally (11Deng L. Liang H. Xu M. Yang X. Burnette B. Arina A. et al.STING-dependent cytosolic DNA sensing promotes radiation-induced type I interferon-dependent antitumor immunity in immunogenic tumors.Immunity. 2014; 41: 843-852Abstract Full Text Full Text PDF PubMed Scopus (1190) Google Scholar, 12Liu X. Pu Y. Cron K. Deng L. Kline J. Frazier W.A. et al.CD47 blockade triggers T cell–mediated destruction of immunogenic tumors.Nat. Med. 2015; 21: 1209-1215Crossref PubMed Scopus (492) Google Scholar). When DNA spills out into the cytoplasm due to chromosomal instability in tumor cells or dead tumor cells phagocytosed by macrophages, the intracellular STING signaling pathway will be activated to initiate antitumor immunity (13Corrales L. Gajewski T.F. Endogenous and pharmacologic targeting of the STING pathway in cancer immunotherapy.Cytokine. 2016; 77: 245-247Crossref PubMed Scopus (30) Google Scholar). Activation of the STING pathway by intratumoral injection of cGAMP or its analogs results in enhanced antitumor effects of CD8+ T cells, significantly inhibits tumor growth, and prolongs the survival period. Combination of cGAMP with immune system checkpoint inhibitors or radiotherapy results in promising antitumor effects (14Demaria O. De Gassart A. Coso S. Gestermann N. Di Domizio J. Flatz L. et al.STING activation of tumor endothelial cells initiates spontaneous and therapeutic antitumor immunity.Proc. Natl. Acad. Sci. U. S. A. 2015; 112: 15408-15413Crossref PubMed Scopus (320) Google Scholar). Taken together, these results suggested that the STING pathway is essential for tumor immune surveillance and antitumor immunity. Besides, Yang H et al. found that intratumoral STING activation delays tumor growth and suppresses lung metastasis in spontaneous cancer models by upregulating type-I IFN genes and vascular stabilizing genes (15Yang H. Lee W.S. Kong S.J. Kim C.G. Kim J.H. Chang S.K. et al.STING activation reprograms tumor vasculatures and synergizes with VEGFR2 blockade.J. Clin. Invest. 2019; 129: 4350-4364Crossref PubMed Scopus (125) Google Scholar). In addition, STING represses the induction and expansion of myeloid-derived suppressor cells via inhibition of CSF2 and IL-6 expression in Epstein-Barr virus–associated nasopharyngeal carcinoma, leading to better patient prognosis (16Zhang C. Ye S. Ni J. Cai T. Liu Y. Huang D. et al.STING signaling remodels the tumor microenvironment by antagonizing myeloid-derived suppressor cell expansion.Cell Death Differ. 2019; 26: 2314-2328Crossref PubMed Scopus (60) Google Scholar). Moreover, the activation of the STING pathway in cancer is associated with increased CD4+ and CD8+ lymphocytic infiltration, and its activation promotes the migration of peripheral blood mononuclear cells by activating CXCL10 and CCL5 expression (17Parkes E.E. Walker S.M. Taggart L.E. McCabe N. Knight L.A. Wilkinson R. et al.Activation of STING-dependent innate immune signaling by S-Phase-Specific DNA damage in breast cancer.JNCI J. Natl. Cancer Inst. 2017; 109: djw199Crossref PubMed Scopus (276) Google Scholar). Collectively, the STING pathway has been established to play a significant role in anticancer immunity mediated by various cytokines (11Deng L. Liang H. Xu M. Yang X. Burnette B. Arina A. et al.STING-dependent cytosolic DNA sensing promotes radiation-induced type I interferon-dependent antitumor immunity in immunogenic tumors.Immunity. 2014; 41: 843-852Abstract Full Text Full Text PDF PubMed Scopus (1190) Google Scholar, 18Khoo L.T. Chen L. Role of the cGAS–STING pathway in cancer development and oncotherapeutic approaches.EMBO Rep. 2018; https://doi.org/10.15252/embr.201846935Crossref PubMed Scopus (81) Google Scholar, 19Ng K.W. Marshall E.A. Bell J.C. Lam W.L. cGAS–STING and cancer: dichotomous roles in tumor immunity and development.Trends Immunol. 2018; 39: 44-54Abstract Full Text Full Text PDF PubMed Scopus (130) Google Scholar). However, secreted proteins regulated by the STING pathway are incompletely known, which warrants further studies. This study aimed to identify secretory proteins regulated by the STING pathway and explore their effects on cancer. We utilized tandem mass tag (TMT)-labeled quantitative proteomics to identify the profile of secretory proteins after STING pathway activation. Twenty-four secretory proteins were identified to be significantly regulated by STING; most of these have not been reported in other literature. Furthermore, activation of the STING pathway inhibited the migration and invasion of cancer cells by suppressing PLAU expression. Our findings reveal the mechanism underlying the repressive effect of the STING pathway on tumorigenesis and progression, providing the foothold for the development of future therapeutic approaches. Multiple studies have shown that the STING signaling pathway affects tumor development through secretory proteins such as CXCL10, CCL5, and IFNs (15Yang H. Lee W.S. Kong S.J. Kim C.G. Kim J.H. Chang S.K. et al.STING activation reprograms tumor vasculatures and synergizes with VEGFR2 blockade.J. Clin. Invest. 2019; 129: 4350-4364Crossref PubMed Scopus (125) Google Scholar, 17Parkes E.E. Walker S.M. Taggart L.E. McCabe N. Knight L.A. Wilkinson R. et al.Activation of STING-dependent innate immune signaling by S-Phase-Specific DNA damage in breast cancer.JNCI J. Natl. Cancer Inst. 2017; 109: djw199Crossref PubMed Scopus (276) Google Scholar). However, the recognition of the secreted proteins regulated by the STING signaling pathway is incomplete. Herein, we utilized HFF cells as a normal cell type to study the secreted proteins regulated by the STING signaling pathway. As illustrated in Figure 1A, we utilized cGAMP to activate the STING pathway and then conducted a TMT-labeled quantitative proteomic analysis to identify the secretory proteins regulated by the STING pathway. We confirmed the activation of STING via immunoblotting before performing mass spectral sample processing (Fig. 1B). The proteomic analysis identified a total of 1782 proteins, of which the expression levels of 1651 proteins were quantified. Gene Ontology (GO) cellular component enrichment analysis of the 1651 proteins showed that most of the quantified proteins are located in the extracellular region, vesicle, and extracellular space (Fig. 1C), indicating the quantified proteins are secreted proteins. Unsupervised clustering by principal component analysis showed that the quantified secretory proteins from the cGAMP group and control group were well separated (Fig. S1D). Taken together, these results substantiated the reliability and validity of our experimental method and data. During the comparison of the cGAMP group versus the control group, the quantified 1651 proteins were tested with one-way ANOVA, and the differentially expressed proteins (DEPs) screening criteria were set as |log2FC| > 0.585, p < 0.05. A total of 24 DEPs were obtained (Fig. 1D), of which 19 and 5 DEPs were significantly upregulated and downregulated, respectively, the change tendency of DEPs is displayed in a volcano plot (Fig. 1E). The four upregulated DEPs, including IFNλ1, IFNβ1, CCL5, and CXCL10, have been documented to be encoded by classical STING pathway downstream response genes, which demonstrated the reliability of the results of the proteomics analysis (17Parkes E.E. Walker S.M. Taggart L.E. McCabe N. Knight L.A. Wilkinson R. et al.Activation of STING-dependent innate immune signaling by S-Phase-Specific DNA damage in breast cancer.JNCI J. Natl. Cancer Inst. 2017; 109: djw199Crossref PubMed Scopus (276) Google Scholar, 20Hsin F. Hsu Y.-C. Tsai Y.-F. Lin S.-W. Liu H.M. The transmembrane serine protease hepsin suppresses type I interferon induction by cleaving STING.Sci. Signal. 2021; 14: eabb4752Crossref PubMed Scopus (4) Google Scholar). Notably, most of the remaining secretory proteins have not been reported to be regulated by the STING pathway. To investigate the biological function of DEPs, we analyzed these 24 DEPs by KEGG and GO pathway enrichment analysis. KEGG pathway analysis showed that the DEPs were significantly enriched in pathways related to the following biological processes: cytokine-cytokine receptor interaction, innate immunity signaling pathways, and inflammation-related pathways (Fig. S1A). GO annotation indicated that the DEPs were significantly enriched in biological processes, including the immune response, inflammatory response, and regulation of cell proliferation, and molecular functions including cytokine activity and chemokine activity (Fig. S1B). In addition, we examined the mRNA expression level of genes encoding DEPs after STING pathway activation (Fig. S2). To our surprise, there was no significant difference in mRNA expression of some DEPs after STING signaling pathway activation, suggesting that the STING signaling pathway may regulate certain DEPs expression at the posttranscriptional level. Together, these findings reveal a secretory protein map regulated by STING signaling pathway for the first time and provide a valuable reference for future investigations. Score plots showed that urokinase-type plasminogen activator (PLAU) was the most significant putative downstream target of the STING pathway and mainly accounted for the difference between the control and cGAMP groups (Fig. S1C). PLAU, a serine peptidase, which is frequently overexpressed in numerous cancers, participates in the degradation of the extracellular matrix and contributes to cancer cell metastasis (21Carlin S.M. Resink T.J. Tamm M. Roth M. Urokinase signal transduction and its role in cell migration.FASEB J. 2005; 19: 195-202Crossref PubMed Scopus (37) Google Scholar, 22Hildenbrand R. Allgayer H. Marx A. Stroebel P. Modulators of the urokinase-type plasminogen activation system for cancer.Expert Opin. Investig. Drugs. 2010; 19: 641-652Crossref PubMed Scopus (67) Google Scholar, 23Deryugina E.I. Quigley J.P. Cell surface remodeling by plasmin: a new function for an old enzyme.J. Biomed. Biotechnol. 2012; 2012: 564259Crossref PubMed Scopus (128) Google Scholar). To further evaluate the clinical correlation between PLAU and cancer, we performed expression analyses based on GEPIA2 (gepia2.cancer-pku.cn) and found that PLAU is highly expressed in breast cancer, lung cancer, gastric cancer, and other malignant cancers (Fig. S1E). Most importantly, PLAU was highly expressed in triple-negative breast cancer (TNBC) (Fig. 2A), a subtype of basal-like breast cancer that does not express ER, PR, and HER2, with high invasiveness and high metastatic potential (24Barzaman K. Karami J. Zarei Z. Hosseinzadeh A. Kazemi M.H. Moradi-Kalbolandi S. et al.Breast cancer: biology, biomarkers, and treatments.Int. Immunopharmacol. 2020; 84106535Crossref PubMed Scopus (163) Google Scholar). Notably, a 10-year follow-up biomarker-based prospective phase III trial validated the predictive and prognostic effect of PLAU in breast cancer (25Harbeck N. Schmitt M. Meisner C. Friedel C. Untch M. Schmidt M. et al.Ten-year analysis of the prospective multicentre Chemo-N0 trial validates American Society of Clinical Oncology (ASCO)-recommended biomarkers uPA and PAI-1 for therapy decision making in node-negative breast cancer patients.Eur. J. Cancer. 2013; 49: 1825-1835Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar). Several studies have demonstrated that reducing PLAU expression in breast cancer is an effective treatment (23Deryugina E.I. Quigley J.P. Cell surface remodeling by plasmin: a new function for an old enzyme.J. Biomed. Biotechnol. 2012; 2012: 564259Crossref PubMed Scopus (128) Google Scholar, 24Barzaman K. Karami J. Zarei Z. Hosseinzadeh A. Kazemi M.H. Moradi-Kalbolandi S. et al.Breast cancer: biology, biomarkers, and treatments.Int. Immunopharmacol. 2020; 84106535Crossref PubMed Scopus (163) Google Scholar, 25Harbeck N. Schmitt M. Meisner C. Friedel C. Untch M. Schmidt M. et al.Ten-year analysis of the prospective multicentre Chemo-N0 trial validates American Society of Clinical Oncology (ASCO)-recommended biomarkers uPA and PAI-1 for therapy decision making in node-negative breast cancer patients.Eur. J. Cancer. 2013; 49: 1825-1835Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar). We detected the expression level of PLAU in different breast cancer cell lines and found that PLAU was highly expressed in TNBC cell line MDA-MB-231, while the expression level was very low in MCF7 and other breast cancer cells (Fig. 2B). We stimulated the STING pathway in MDA-MB-231 cells with the STING agonists, cGAMP and diABZI, respectively. The results indicated that both cGAMP and diABZI successfully activated the STING signaling pathway and reduced PLAU protein expression in MDA-MB-231 cells (Figs. 2E and S3C). However, PLAU mRNA reduction was minor compared to protein, suggesting the STING signaling pathway may affect the synthesis or degradation of PLAU protein (Fig. S3, A and B). Therefore, we examined whether STING activation affects the degradation/synthesis of PLAU protein. Firstly, we blocked the proteasome degradation pathway and the autophagy pathway, respectively; the results showed that the PLAU protein is degraded by the autophagy pathway in MDA-MB-231 cells (Fig. 2, C and D). Meanwhile, the previous study has shown that activation of the STING signaling pathway triggers autophagy (5Gui X. Yang H. Li T. Tan X. Shi P. Li M. et al.Autophagy induction via STING trafficking is a primordial function of the cGAS pathway.Nature. 2019; 567: 262-266Crossref PubMed Scopus (473) Google Scholar). We activated STING signaling pathway after treatment with chloroquine and found that STING activation reduced PLAU expression even after blocking autophagy (Fig. 2F). These results suggest that activation of the STING pathway does not inhibit the expression of PLAU by triggering autophagy degradation of PLAU protein in MDA-MB-231 cells. To explore the underlying mechanism of the STING pathway in regulating PLAU expression, we knocked out STING in MDA-MB-231 cells (Fig. S3D). In control cells, the activation of the STING signaling pathway suppressed the expression of PLAU but the reduction of PLAU was abolished in STING KO MDA-MB-231 cells (Fig. 3, A and B). Dan Zhang et al. recently identified a previously unrecognized nonclassical STING signaling pathway that controls mRNA cap-dependent translation (26Zhang D. A non-canonical cGAS–STING–PERK pathway facilitates the translational program critical for senescence and organ fibrosis.NatUre Cell Biol. 2022; 24: 35Crossref PubMed Scopus (33) Google Scholar). Briefly, upon binding with cGAMP, STING directly interacts with PKR-like ER kinase (PERK) and activates PERK-eukaryotic initiation factor 2α (eIF2α) signal axis, which precedes TBK1-IRF3 activation and independent of unfolded protein response and autophagy. PERK phosphorylates eIF2α at its conserved residue S51, resulting in a reduction of overall protein synthesis (27Zhou D. Palam L.R. Jiang L. Narasimhan J. Staschke K.A. Wek R.C. Phosphorylation of eIF2 directs ATF5 translational control in response to diverse stress conditions.J. Biol. Chem. 2008; 283: 7064-7073Abstract Full Text Full Text PDF PubMed Scopus (206) Google Scholar). Thus, we hypothesized that the STING-PERK-eIF2α signaling axis mediates the translation regulation of PLAU. We examined the capability of STING to trigger phospho-eIF2α S51 upon binding with cGAMP in MDA-MB-231 cells. Notably, we observed a robust, time-dependent phospho-eIF2α signal, which precedes TBK1-IRF3 activation (Fig. 3C). STING agonist diABZI also triggered the prominent phosphorylation of endogenous eIF2α in a STING-dependent manner in MDA-MB-231 cells (Fig. 3D). These results verify a functional STING-PERK-eIF2α signal axis in MDA-MB-231 cells. Activated PERK phosphorylates eIF2α at its S51 residue (28Donnelly N. Gorman A.M. Gupta S. Samali A. The eIF2α kinases: their structures and functions.Cell Mol. Life Sci. 2013; 70: 3493-3511Crossref PubMed Scopus (537) Google Scholar). We utilized pharmacological PERK inhibitors GSK2606414 (iPERK-1) and GSK2656157 (iPERK-2) to eliminate STING-initiated phospho-PERK T982 and phospho-eIF2α S51. As illustrated in Figure 3E, the results indicated that cGAMP activates the STING-PERK-eIF2α signaling axis and results in significant repression of PLAU, which was abrogated by PERK inhibitors. These results suggest that the STING-PERK-eIF2α signaling pathway is responsible for STING-dependent PLAU reduction. PLAU performs as a protease and participates in the transition of plasminogen to plasmin, which results in extracellular matrix remodeling, release, and activation of growth factors (29Duffy M. The urokinase plasminogen activator system: role in malignancy.CPD. 2004; 10: 39-49Crossref Scopus (350) Google Scholar, 30Danø K. Behrendt N. Høyer-Hansen G. Johnsen M. Lund L.R. Ploug M. et al.Plasminogen activation and cancer.Thromb. Haemost. 2005; 93: 676-681Crossref PubMed Scopus (392) Google Scholar). Besides, abysmal patient outcomes in several types of cancers are frequently accompanied by upregulated expression of PLAU (31Ma J. Qi G. Xu J. Ni H. Xu W. Ru G. et al.Overexpression of forkhead box M1 and urokinase-type plasminogen activator in gastric cancer is associated with cancer progression and poor prognosis.Oncol. Lett. 2017; 14: 7288-7296PubMed Google Scholar). Thus, we further investigated the effects of aberrant expression of PLAU on breast cancer cells by stably overexpressing and knocking out PLAU (Fig. S4, A–D). Overexpression of PLAU in MCF7 and ZR-75-1 cells with low PLAU expression significantly enhanced cell migration ability (Figs. 4A and S3, E and F). Whereas, MCF7 and ZR-75-1 cells cannot invade through the matrigel. Transwell assays indicated that the migration and invasion abilities were significantly increased in PLAU-overexpressing MDA-MB-231 cells and were blunted in PLAU KO MDA-MB-231 cells (Fig. 4, B–E). Besides, overexpression of PLAU slightly increased the proliferation rate of MDA-MB-231 cells while KO of PLAU did not affect the proliferation of MDA-MB-231 cells, indicating PLAU does not affect MDA-MB-231 cells proliferation (Fig. S4, G–L). The data indicate that PLAU is responsible for cancer cell migration and invasion. Studies about the STING signal pathway usually focus on the immune microenvironment but the effect of the STING signal pathway on tumor cells is not clear. Here, we investigated the effect of STING pathway activation on the proliferation, migration, invasion, and colony formation of MDA-MB-231 cells. Cell counting kit-8 (CCK8) and EdU assay results indicated that the effect of STING activation on MDA-MB-231 cell proliferation is minor (Fig. S5, A–C). As PLAU knockdown shows no effect on MDA-MB-231 cell proliferation, we concluded that STING does not affect cell proliferation via PLAU repression. Except for proliferative capacity, the rate of clone formation also reflects the population dependence of the cells. STING pathway activation also effectively repressed colony formation, suggesting that STING pathway activation increases the population dependence of MDA-MB-231 cells (Fig. S5D). Whereas, PLAU overexpression did not restore the repression induced by STING pathway activation on colony formation, indicating that STING does not affect population dependence of MDA-MB-231 cells by inhibiting PLAU expression (Fig. S5, E and F). Notably, the transwell assay showed that STING pathway activation inhibits the migration and invasion of MDA-MB-231 cells (Fig. 5, A and B, E–F). Next, we examined whether the STING pathway affects the migration and invasive abilities of MDA-MB-231 cells through repressing PLAU. The results indicated that activation of the STING pathway significantly inhibited the migration and invasion of MDA-MB-231 cells, while the repression was reversed under the circumstance where MDA-MB-231 cells overexpress PLAU (Fig. 5, C and D, G–H). The results suggest that the activation of the STING pathway inhibited MDA-MB-231 cell migration and invasion by suppressing PLAU expression, providing a novel insight into the mechanism of cancer suppression mediated by the STING signaling pathway. Overall, this study addresses an as-yet unmet need in understanding STING-regulated secreted proteins, other than cytokines, that might play a role in its antitumor activity. Besides, we substantiated that activation of the STING pathway inhibits the migration and invasion of cancer cells by reducing the expression of the secretory protein PLAU. Since activation of the STING pathway fails to promote IFNβ expression in MDA-MB-231 cells, it can be excluded that the aforementioned effects are due to IFNβ. It has been shown that activating the STING pathway has huge prospects for treating various types of cancers (11Deng L. Liang H. Xu M. Yang X. Burnette B. Arina A. et al.STING-dependent cytosolic DNA sensing promotes radiation-induced type I interferon-dependent antitumor immunity in immunogenic tumors.Immunity. 2014; 41: 843-852Abstract Full Text Full Text PDF PubMed Scopus (1190) Google Scholar, 12Liu X. Pu Y. Cron K. Deng L. Kline J. Frazier W.A. et al.CD47 blockade triggers T cell–mediated destruction of immunogenic tumors.Nat. Med. 2015; 21: 1209-1215Crossref PubMed Scopus (492) Google Scholar, 14Demaria O. De Gassart A. Coso S. Gestermann N. Di Domizio J. Flatz L. et al.STING activation of tumor endothelial cells initiates spontaneous and therapeutic antitumor immunity.Proc. Natl. Acad. Sci. U. S. A. 2015; 112: 15408-15413Crossref PubMed Scopus (320) Google Scholar, 32Li A. Yi M. Qin S. Song Y. Chu Q. Wu K. Activating cGAS-STING pathway for the optimal effect of cancer immunotherapy.J. Hematol. Oncol. 2019; 12: 35Crossref PubMed Scopus (140) Google Scholar). For instance, a clinical trial reported that the combination of STING agonist MIW815 (ADU-S100) with spartalizumab could yield anticancer activity against TNBC and melanoma (33Hu Z. Yang Y. Fang L. Zhou J. Zhang H. Insight into the dichotomous regulation of STING activation in immunotherapy.Immunopharmacol. Immunotoxicol. 2021; 43: 126-137Crossref PubMed Scopus (1) Google Scholar). PARP inhibitor olaparib inhibits BRCA1-deficient TNBC by activating the secretion of IFNb, CCL5, and CXCL10, as well as the infiltration and activation of CD8 T cells mediated by the STING pathway (34Pantelidou C. Sonzogni O. De Oliveria Taveira M. Mehta A.K. Kothari A. Wang D. et al.PARP inhibitor efficacy depends on CD8 + T-cell recruitment via intratumoral STING pathway activation in BRCA-deficient models of triple-negative breast cancer.Cancer Discov. 2019; 9: 722-737Crossref PubMed Scopus (318) Google Scholar). Activation of STING-dependent pathways by c-di-GMP could overcome immune suppression in metastatic breast cancer (35Chandra D. Quispe-Tintaya W. Jahangir A. Asafu-Adjei D. Ramos I. Sintim H.O. et al.STING ligand c-di-GMP improves cancer vaccination against metastatic breast cancer.Cancer Immunol. Res. 2014; 2: 901-910Crossref PubMed Scopus (163) Google Scholar). However, most studies on the anticancer mechanism of the STING pathway have focused on cytokines and the immune microenvironment. Herein, we found that activation of the STING pathway represses PLAU translation through the PERK-eIF2α axis. PLAU has been reported to promote the escape, metastasis, and diffusion of human prostate cancer cells in vivo a" @default.
• W4311115652 created "2022-12-23" @default.
• W4311115652 creator A5029304107 @default.
• W4311115652 creator A5029695574 @default.
• W4311115652 creator A5054661098 @default.
• W4311115652 creator A5060580745 @default.
• W4311115652 date "2023-01-01" @default.
• W4311115652 modified "2023-10-02" @default.
• W4311115652 title "Proteomics analysis uncovers plasminogen activator PLAU as a target of the STING pathway for suppression of cancer cell migration and invasion" @default.
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• W4311115652 doi "https://doi.org/10.1016/j.jbc.2022.102779" @default.
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