Cytosolic DNA initiates a vicious circle of aging-related endothelial inflammation and mitochondrial dysfunction via STING: the inhibitory effect of Cilostazol.

Endothelial senescence, aging-related inflammation, and mitochondrial dysfunction are prominent features of vascular aging and contribute to the development of aging-associated vascular disease. Accumulating evidence indicates that DNA damage occurs in aging vascular cells, especially in endothelial cells (ECs). However, the mechanism of EC senescence has not been completely elucidated, and so far, there is no specific drug in the clinic to treat EC senescence and vascular aging. Here we show that various aging stimuli induce nuclear DNA and mitochondrial damage in ECs, thus facilitating the release of cytoplasmic free DNA (cfDNA), which activates the DNA-sensing adapter protein STING. STING activation led to a senescence-associated secretory phenotype (SASP), thereby releasing pro-aging cytokines and cfDNA to further exacerbate mitochondrial damage and EC senescence, thus forming a vicious circle, all of which can be suppressed by STING knockdown or inhibition. Using next-generation RNA sequencing, we demonstrate that STING activation stimulates, whereas STING inhibition disrupts pathways associated with cell senescence and SASP. In vivo studies unravel that endothelial-specific Sting deficiency alleviates aging-related endothelial inflammation and mitochondrial dysfunction and prevents the development of atherosclerosis in mice. By screening FDA-approved vasoprotective drugs, we identified Cilostazol as a new STING inhibitor that attenuates aging-related endothelial inflammation both in vitro and in vivo. We demonstrated that Cilostazol significantly inhibited STING translocation from the ER to the Golgi apparatus during STING activation by targeting S162 and S243 residues of STING. These results disclose the deleterious effects of a cfDNA-STING-SASP-cfDNA vicious circle on EC senescence and atherogenesis and suggest that the STING pathway is a promising therapeutic target for vascular aging-related diseases. A proposed model illustrates the central role of STING in mediating a vicious circle of cfDNA-STING-SASP-cfDNA to aggravate age-related endothelial inflammation and mitochondrial damage.

STAT3ß Enhances Sensitivity to Concurrent Chemoradiotherapy by Inducing Cellular Necroptosis in Esophageal Squamous Cell Carcinoma.

Concurrent chemoradiotherapy (CCRT), especially platinum plus radiotherapy, is considered to be one of the most promising treatment modalities for patients with advanced esophageal cancer. STAT3ß regulates specific target genes and inhibits the process of tumorigenesis and development. It is also a good prognostic marker and a potential marker for response to adjuvant chemoradiotherapy (ACRT). We aimed to investigate the relationship between STAT3ß and CCRT. We examined the expression of STAT3α and STAT3ß in pretreatment tumor biopsies of 105 ESCC patients who received CCRT by immunohistochemistry. The data showed that ESCC patients who demonstrate both high STAT3α expression and high STAT3ß expression in the cytoplasm have a significantly better survival rate, and STAT3ß expression is an independent protective factor (HR = 0.424, p = 0.003). Meanwhile, ESCC patients with high STAT3ß expression demonstrated a complete response to CCRT in 65 patients who received platinum plus radiation therapy (p = 0.014). In ESCC cells, high STAT3ß expression significantly inhibits the ability of colony formation and cell proliferation, suggesting that STAT3ß enhances sensitivity to CCRT (platinum plus radiation therapy). Mechanistically, through RNA-seq analysis, we found that the TNF signaling pathway and necrotic cell death pathway were significantly upregulated in highly expressed STAT3ß cells after CCRT treatment. Overall, our study highlights that STAT3ß could potentially be used to predict the response to platinum plus radiation therapy, which may provide an important insight into the treatment of ESCC.

STAT3ß disrupted mitochondrial electron transport chain enhances chemosensitivity by inducing pyroptosis in esophageal squamous cell carcinoma.

The clinical efficacy of cisplatin in the treatment of esophageal squamous cell carcinoma (ESCC) is undesirable. Signal transducer and activator of transcription 3ß (STAT3ß), a splice variant of STAT3, restrains STAT3α activity and enhances chemosensitivity in ESCC. However, the underlying molecular mechanisms remain poorly understood. Here, we found that high expression of STAT3ß contributes to cisplatin sensitivity and enhances Gasdermin E (GSDME) dependent pyroptosis in ESCC cells after exposure to cisplatin. Mechanistically, STAT3ß was located into the mitochondria and its high expression disrupts the activity of the electron transport chain, resulting in an increase of ROS in cisplatin treatment cells. While high levels of ROS caused activation of caspase-3 and GSDME, and induced cell pyroptosis. STAT3ß blocked the phosphorylation of STAT3α S727 in mitochondria by interacting with ERK1/2 following cisplatin treatment, disrupting electron transport chain and inducing activation of GSDME. Clinically, high expression of both STAT3ß and GSDME was strongly associated with better overall survival and disease-free survival of ESCC patients. Overall, our study reveals that STAT3ß sensitizes ESCC cells to cisplatin by disrupting mitochondrial electron transport chain and enhancing pyroptosis, which demonstrates the prognostic significance of STAT3ß in ESCC therapy.

STAT3, the Challenge for Chemotherapeutic and Radiotherapeutic Efficacy.

Chemoradiotherapy is one of the most effective and extensively used strategies for cancer treatment. Signal transducer and activator of transcription 3 (STAT3) regulates vital biological processes, such as cell proliferation and cell growth. It is constitutively activated in various cancers and limits the application of chemoradiotherapy. Accumulating evidence suggests that STAT3 regulates resistance to chemotherapy and radiotherapy and thereby impairs therapeutic efficacy by mediating its feedback loop and several target genes. The alternative splicing product STAT3ß is often identified as a dominant-negative regulator, but it enhances sensitivity to chemotherapy and offers a new and challenging approach to reverse therapeutic resistance. We focus here on exploring the role of STAT3 in resistance to receptor tyrosine kinase (RTK) inhibitors and radiotherapy, outlining the potential of targeting STAT3 to overcome chemo(radio)resistance for improving clinical outcomes, and evaluating the importance of STAT3ß as a potential therapeutic approach to overcomes chemo(radio)resistance. In this review, we discuss some new insights into the effect of STAT3 and its subtype STAT3ß on chemoradiotherapy sensitivity, and we explore how these insights influence clinical treatment and drug development for cancer.

STAT3beta, a distinct isoform from STAT3.

STAT3ß is an isoform of STAT3 (signal transducer and activator of transcription 3) that differs from the STAT3α isoform by the replacement of the C-terminal 55 amino acid residues with 7 specific residues. The constitutive activation of STAT3α plays a pivotal role in the activation of oncogenic pathways, such as cell proliferation, maturation and survival, while STAT3ß is often referred to as a dominant-negative regulator of cancer. STAT3ß reveals a "spongy cushion" effect through its cooperation with STAT3α or forms a ternary complex with other co-activators. Especially in tumour cells, relatively high levels of STAT3ß lead to some favourable changes. However, there are still many mechanisms that have not been clearly explained in contrast to STAT3α, such as STAT3ß nuclear retention, more stable heterodimers and the prolonged Y705 phosphorylation. In addition to its transcriptional activities, STAT3ß may also function in the cytosol with respect to the mitochondria, cytoskeleton rearrangements and metastasis of cancer cells. In this review, we summarize the mechanisms that underlie the unique roles of STAT3ß combined with total STAT3 to enlighten and draw the attention of researchers studying STAT3 and discuss some interesting questions that warrant answers.