Approaching non-canonical STAT3 signaling to redefine cancer therapeutic strategy

Dimri, Shalini; Sukanya, .; De, Abhijit

doi:10.15761/imm.1000268

Cited by 8 publications

(7 citation statements)

References 80 publications

(97 reference statements)

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“…Although the STAT family proteins are encoded by separate genes, they share a common set of structural domains that show functional similarities [33,42]. STAT3 can be activated in a paracrine manner by upstream regulators such as receptor- and non-receptor-associated kinases, including JAKs, Akt, Src family kinases, and MAP kinases [15,43]. Because the STAT family proteins and their upstream regulators can crosstalk with other signaling pathways associated with normal physiological functions, non-selective STAT3 inhibitors can influence normal physiological functions.…”

Section: Discussionmentioning

confidence: 99%

Development of Oxadiazole-Based ODZ10117 as a Small-Molecule Inhibitor of STAT3 for Targeted Cancer Therapy

Kim

Lee

Song

et al. 2019

JCM

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Persistently activated STAT3 is a promising target for a new class of anticancer drug development and cancer therapy, as it is associated with tumor initiation, progression, malignancy, drug resistance, cancer stem cell properties, and recurrence. Here, we discovered 3-(2,4-dichloro-phenoxymethyl)-5-trichloromethyl-[1,2,4]oxadiazole (ODZ10117) as a small-molecule inhibitor of STAT3 to be used in STAT3-targeted cancer therapy. ODZ10117 targeted the SH2 domain of STAT3 regardless of other STAT family proteins and upstream regulators of STAT3, leading to inhibition of the tyrosine phosphorylation, dimerization, nuclear translocation, and transcriptional activity of STAT3. The inhibitory effect of ODZ10117 on STAT3 was stronger than the known STAT3 inhibitors such as S3I-201, STA-21, and nifuroxazide. ODZ10117 suppressed the migration and invasion, induced apoptosis, reduced tumor growth and lung metastasis, and extended the survival rate in both in vitro and in vivo models of breast cancer. Overall, we demonstrated that ODZ10117 is a novel STAT3 inhibitor and may be a promising agent for the development of anticancer drugs.

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Section: Discussionmentioning

confidence: 99%

Development of Oxadiazole-Based ODZ10117 as a Small-Molecule Inhibitor of STAT3 for Targeted Cancer Therapy

Kim

Lee

Song

et al. 2019

JCM

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“…In addition, we evaluated the effects of 1 MHz US on the protein expression levels of STAT3. It is well known that STAT3 and NF-κB can cooperate to promote the target gene expression, and many cytokines, such as IL-6, can induce a feedback on STAT3 and NF-κB 49 , 50 . As reported in Figure S2 of ESI, we observed a decrease in the phosphorylated (p)-STAT3/STAT3 ratio after 1 h exposure at I spta = 65 mW/cm 2 , followed by 15 min of recovery, with a slight increase after 3 h of recovery (further details are reported in Section S2 of ESI).…”

Section: Resultsmentioning

confidence: 99%

Effect of 1-MHz ultrasound on the proinflammatory interleukin-6 secretion in human keratinocytes

Giantulli

Tortorella

Brasili

et al. 2021

Sci Rep

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Keratinocytes, the main cell type of the skin, are one of the most exposed cells to environmental factors, providing a first defence barrier for the host and actively participating in immune response. In fact, keratinocytes express pattern recognition receptors that interact with pathogen associated molecular patterns and damage associated molecular patterns, leading to the production of cytokines and chemokines, including interleukin (IL)-6. Herein, we investigated whether mechanical energy transported by low intensity ultrasound (US) could generate a mechanical stress able to induce the release of inflammatory cytokine such IL-6 in the human keratinocyte cell line, HaCaT. The extensive clinical application of US in both diagnosis and therapy suggests the need to better understand the related biological effects. Our results point out that US promotes the overexpression and secretion of IL-6, associated with the activation of nuclear factor-κB (NF-κB). Furthermore, we observed a reduced cell viability dependent on exposure parameters together with alterations in membrane permeability, paving the way for further investigating the molecular mechanisms related to US exposure.

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“…STAT3 is an essential transcription factor that activates a cascade of survival and proliferation signaling programs in cells. Expression of phosphorylated (p)-STAT3 is an important factor related to tumor invasion and poor prognosis (46,47). Furthermore, CXCR7-induced STAT3-mediated pathways may enhance tumor growth by regulating cell proliferative pathways; STAT3 signaling is associated with the upregulation of cyclin and c-MYC expression, contributing to accelerated cell cycle progression (17,48).…”

Section: Discussionmentioning

confidence: 99%

Decursin inhibits tumor progression in head and neck squamous cell carcinoma by downregulating CXCR7 expressionin vitro

et al. 2021

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CXC chemokine receptor 7 (CXCR7) is frequently overexpressed in cancer and plays a significant role in tumor growth and metastasis. Consequently, inhibition of CXCR7 is important for treatment strategies. However, little is known concerning the biological role of CXCR7 and its underlying mechanisms in head and neck squamous cell carcinoma (HNSCC). The present study investigated the role of CXCR7 in HNSCC, as well as the effects of decursin, a pyranocoumarin compound isolated from Angelica gigas Nakai, on CXCR7 and its downstream signaling. Expression levels of CXCR7 in HNSCC cells were examined using flow cytometry, reverse transcriptase PCR, western blot analysis, and immunofluorescence. The effects of CXCR7 on cell proliferation, migration, and invasion were studied using CCK-8, gap closure, and transwell assays. The results revealed that decursin significantly reduced CXCR7 expression and inhibited cell proliferation, migration, and invasion of human HNSCC cell lines. In addition, decursin induced G0/G1 cell cycle arrest in CXCR7-overexpressing cells and decreased the levels of cyclin A, cyclin E, and CDK2. Furthermore, CXCR7 promoted cancer progression via the STAT3/c-Myc pathway in HNSCC; suppression of CXCR7 with decursin prevented this effect. These results suggest that CXCR7 promotes cancer progression through the STAT3/c-Myc pathway and that the natural compound decursin targets CXCR7 and may be valuable in the treatment of HNSCC.

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Approaching non-canonical STAT3 signaling to redefine cancer therapeutic strategy

Cited by 8 publications

References 80 publications

Development of Oxadiazole-Based ODZ10117 as a Small-Molecule Inhibitor of STAT3 for Targeted Cancer Therapy

Development of Oxadiazole-Based ODZ10117 as a Small-Molecule Inhibitor of STAT3 for Targeted Cancer Therapy

Effect of 1-MHz ultrasound on the proinflammatory interleukin-6 secretion in human keratinocytes

Decursin inhibits tumor progression in head and neck squamous cell carcinoma by downregulating CXCR7 expressionin vitro

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