Molecular disruption of oncogenic signal transducer and activator of transcription 3 (STAT3) protein

2009 ◽  
Vol 87 (6) ◽  
pp. 825-833 ◽  
Author(s):  
Steven Fletcher ◽  
Joel A. Drewry ◽  
Vijay M. Shahani ◽  
Brent D. G. Page ◽  
Patrick T. Gunning
Keyword(s):  
Transcriptional Activity ◽  
Protein Complexes ◽  
Signal Transducer ◽  
Cellular Functions ◽  
Protein Activity ◽  
Upstream Kinase ◽  
Cancer Phenotype ◽  
Stat3 Signalling ◽  
Transcription 3 ◽  
Uncontrolled Cell Proliferation

Signal transducer and activator of transcription protein 3 (STAT3) is a latent cytosolic transcription factor that is widely recognized as being a master regulator of the cellular functions that lead to the cancer phenotype. Constitutively activated STAT3 protein activity is routinely observed in human cancers, promoting uncontrolled cell proliferation and suppressing apoptosis. Until relatively recently, inhibition of STAT3 transcriptional activity was achieved indirectly via suppression of upstream kinase activators and extracellular cytokine and (or) growth factor stimuli. However, activated STAT3 forms transcriptionally functional STAT3–STAT3 dimers, providing a valid juncture for targeted downstream molecular inhibition. STAT3's prominent role in cancer has seen a decade of innovative and novel approaches to targeting constitutively active STAT3 protein–protein complexes. This mini-review outlines the progress made towards identifying molecular agents capable of silencing aberrant STAT3 signalling through the disruption of STAT3 complexation events.

scholarly journals An Electrophilic Deguelin Analogue Inhibits STAT3 Signaling in H-Ras-Transformed Human Mammary Epithelial Cells: The Cysteine 259 Residue as a Potential Target

Biomedicines ◽  
2020 ◽  
Vol 8 (10) ◽  
pp. 407 ◽  
Author(s):  
Sung-Jun Hong ◽  
Jin-Tae Kim ◽  
Su-Jung Kim ◽  
Nam-Chul Cho ◽  
Kyeojin Kim ◽  
...  
Keyword(s):  
Stromal Cells ◽  
Transcriptional Activity ◽  
Nuclear Translocation ◽  
Mammary Epithelial Cells ◽  
Mammary Epithelial ◽  
Transformed Cells ◽  
Signal Transducer ◽  
Stat3 Signaling ◽  
Human Mammary Epithelial ◽  
Transcription 3

Signal transducer and activator of transcription 3 (STAT3) is a point of convergence for numerous oncogenic signals that are often constitutively activated in many cancerous or transformed cells and some stromal cells in the tumor microenvironment. Persistent STAT3 activation in malignant cells stimulates proliferation, survival, angiogenesis, invasion, and tumor-promoting inflammation. STAT3 undergoes activation through phosphorylation on tyrosine 705, which facilitates its dimerization. Dimeric STAT3 translocates to the nucleus, where it regulates the transcription of genes involved in cell proliferation, survival, etc. In the present study, a synthetic deguelin analogue SH48, discovered by virtual screening, inhibited the phosphorylation, nuclear translocation, and transcriptional activity of STAT3 in H-ras transformed human mammary epithelial MCF-10A cells (MCF10A-ras). We speculated that SH48 bearing an α,β-unsaturated carbonyl group could interact with a thiol residue of STAT3, thereby inactivating this transcription factor. Non-electrophilic analogues of SH48 failed to inhibit STAT3 activation, lending support to the above supposition. By utilizing a biotinylated SH48, we were able to demonstrate the complex formation between SH48 and STAT3. SH48 treatment to MCF10A-ras cells induced autophagy, which was verified by staining with a fluorescent acidotropic probe, LysoTracker Red, as well as upregulating the expression of LC3II and p62. In conclusion, the electrophilic analogue of deguelin interacts with STAT3 and inhibits its activation in MCF10A-ras cells, which may account for its induction of autophagic death.

scholarly journals Acetylated Signal Transducer and Activator of Transcription 3 Functions as Molecular Adaptor Independent of Transcriptional Activity During Human Cardiogenesis

Stem Cells ◽  
2017 ◽  
Vol 35 (10) ◽  
pp. 2129-2137 ◽  
Author(s):  
Ashish Mehta ◽  
Chrishan J. A. Ramachandra ◽  
Anuja Chitre ◽  
Pritpal Singh ◽  
Chong Hui Lua ◽  
...  
Keyword(s):  
Transcriptional Activity ◽  
Signal Transducer ◽  
Transcription 3

scholarly journals Induction of caspase-dependent extrinsic apoptosis by apigenin through inhibition of signal transducer and activator of transcription 3 (STAT3) signalling in HER2-overexpressing BT-474 breast cancer cells

2015 ◽  
Vol 35 (6) ◽  
Author(s):  
Hye-Sook Seo ◽  
Jae Kyung Jo ◽  
Jin Mo Ku ◽  
Han-Seok Choi ◽  
Youn Kyung Choi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Signal Transducer ◽  
Stat3 Signaling ◽  
Extrinsic Apoptosis ◽  
Stat3 Signalling ◽  
Transcription 3

Apigenin induced caspase-dependent extrinsic apoptosis through inhibition of STAT3 signaling in HER2 overexpressing BT-474 breast cancer cells.

Hypoxia is a potent inducer of the iron masterswitch hepcidin via Signal Transducer and Activator of Transcription 3 (STAT3)

2017 ◽  
Author(s):  
I Silva ◽  
V Rausch ◽  
T Peccerella ◽  
G Millonig ◽  
HK Seitz ◽  
...  
Keyword(s):  
Signal Transducer ◽  
Potent Inducer ◽  
Transcription 3

Magnesium-dependent Phosphatase (MDP) 1 is a Potential Suppressor of Gastric Cancer

2019 ◽  
Vol 19 (10) ◽  
pp. 817-827
Author(s):  
Jianbo Zhu ◽  
Lijuan Deng ◽  
Baozhen Chen ◽  
Wenqing Huang ◽  
Xiandong Lin ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Dna Methylation ◽  
Cell Proliferation ◽  
Protein C ◽  
Biological Function ◽  
Prognostic Markers ◽  
Biological Effects ◽  
Signal Transducer ◽  
Gastric Cancer Cells ◽  
Transcription 3

Background:Recurrence is the leading cause of treatment failure and death in patients with gastric cancer (GC). However, the mechanism underlying GC recurrence remains unclear, and prognostic markers are still lacking.Methods:We analyzed DNA methylation profiles in gastric cancer cases with shorter survival (<1 year) or longer survival (> 3 years), and identified candidate genes associated with GC recurrence. Then, the biological effects of these genes on gastric cancer were studied.Results:A novel gene, magnesium-dependent phosphatase 1 (mdp1), was identified as a candidate gene whose DNA methylation was higher in GC samples from patients with shorter survival and lower in patients with longer survival. MDP1 protein was highly expressed in GC tissues with longer survival time, and also had a tendency to be expressed in highly differentiated GC samples. Forced expression of MDP1 in GC cell line BGC-823 inhibited cell proliferation, whereas the knockdown of MDP1 protein promoted cell growth. Overexpression of MDP1 in BGC-823 cells also enhanced cell senescence and apoptosis. Cytoplasmic kinase protein c-Jun N-terminal kinase (JNK) and signal transducer and activator of transcription 3 (Stat3) were found to mediate the biological function of MDP1.Conclusion:These results suggest that MDP1 protein suppresses the survival of gastric cancer cells and loss of MDP expression may benefit the recurrence of gastric cancer.

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