Objective:Gastric cancer(GC)is one of the most common malignancies seen in clinic and requires novel treatment options.Morin is a natural flavonoid extracted from the flower stalk of a highly valuable medicinal plant ...Objective:Gastric cancer(GC)is one of the most common malignancies seen in clinic and requires novel treatment options.Morin is a natural flavonoid extracted from the flower stalk of a highly valuable medicinal plant Prunella vulgaris L.,which exhibits an anti-cancer effect in multiple types of tumors.However,the therapeutic effect and underlying mechanism of morin in treating GC remains elusive.The study aims to explore the therapeutic effect and underlying molecular mechanisms of morin in GC.Methods:For in vitro experiments,the proliferation inhibition of morin was measured by cell counting kit-8 assay and colony formation assay in human GC cell line MKN45,human gastric adenocarcinoma cell line AGS,and human gastric epithelial cell line GES-1;for apoptosis analysis,microscopic photography,Western blotting,ubiquitination analysis,quantitative polymerase chain reaction analysis,flow cytometry,and RNA interference technology were employed.For in vivo studies,immunohistochemistry,biomedical analysis,and Western blotting were used to assess the efficacy and safety of morin in a xenograft mouse model of GC.Results:Morin significantly inhibited the proliferation of GC cells MKN45 and AGS in a dose-and timedependent manner,but did not inhibit human gastric epithelial cells GES-1.Only the caspase inhibitor Z-VAD-FMK was able to significantly reverse the inhibition of proliferation by morin in both GC cells,suggesting that apoptosis was the main type of cell death during the treatment.Morin induced intrinsic apoptosis in a dose-dependent manner in GC cells,which mainly relied on B cell leukemia/lymphoma 2(BCL-2)associated agonist of cell death(BAD)but not phorbol-12-myristate-13-acetate-induced protein 1.The upregulation of BAD by morin was due to blocking the ubiquitination degradation of BAD,rather than the transcription regulation and the phosphorylation of BAD.Furthermore,the combination of morin and BCL-2 inhibitor navitoclax(also known as ABT-737)produced a synergistic inhibitory effect in GC cells through amplifying apoptotic signals.In addition,morin treatment significantly suppressed the growth of GC in vivo by upregulating BAD and the subsequent activation of its downstream apoptosis pathway.Conclusion:Morin suppressed GC by inducing apoptosis,which was mainly due to blocking the ubiquitination-based degradation of the pro-apoptotic protein BAD.The combination of morin and the BCL-2 inhibitor ABT-737 synergistically amplified apoptotic signals in GC cells,which may overcome the drug resistance of the BCL-2 inhibitor.These findings indicated that morin was a potent and promising agent for GC treatment.展开更多
The B-cell lymphoma-extra large （Bcl-xL） is a mitochondrial anti-apoptotic protein that plays a role in neuroprotection. However, during excitotoxic stimulation, Bcl-xL undergoes caspase-dependent cleavage and produ...The B-cell lymphoma-extra large （Bcl-xL） is a mitochondrial anti-apoptotic protein that plays a role in neuroprotection. However, during excitotoxic stimulation, Bcl-xL undergoes caspase-dependent cleavage and produces a fragmented form, △N-Bcl-xL. Accumulation of △N-Bcl-xL is associated with mitochon- drial dysfunction and neuronal death. Therefore, strategies to inhibit the activity or formation of △N-Bcl- xL protect the brain against excitotoxic injuries. Our team found that the pharmacological inhibitor △BT- 737 exerts dose dependent effects in primary neurons. When primary hippocampal neurons were treated with 1 μM ABT-737, glutamate-mediated mitochondrial damage and neuronal death were exacerbated, whereas 10 nM △BT-737, a 100-fold lower concentration, protected mitochondrial function and enhanced neuronal viability against glutamate toxicity. In addition, we suggested acute vs. prolonged formation of △N-Bcl-xL may have different effects on mitochondrial or neuronal functions. Unlike acute production of △N-Bcl-xL by glutamate, overexpression of △N-Bcl-xL did not cause drastic changes in neuronal viability. We predicted that neurons undergo adaptation and may activate altered metabolism to compensate for △N-Bcl-xL-mediated mitochondrial dysfunction. Although the detailed mechanism of ABT-mediated neurotoxicity neuroprotection is still unclear, our study shows that the mitochondrial membrane protein △N-Bcl-xL is a central target for interventions.展开更多
Head and neck squamous cell carcinomas (HNSCC) are common human malignancies with poor clinical outcomes. The 5-year survival rates for patients with advanced stage HNSCC have not changed appreciably in the past few d...Head and neck squamous cell carcinomas (HNSCC) are common human malignancies with poor clinical outcomes. The 5-year survival rates for patients with advanced stage HNSCC have not changed appreciably in the past few decades, underscoring a dire need for improved therapeutic options. Recent studies have elucidated a key signaling axis, the EGFR-STAT3-Bcl-XL signaling axis, that is aberrantly activated in a majority of HNSCC and contributes to the proliferation and survival of malignant cells. Considerable effort is being placed on developing highly specific inhibitors of different components of this pathway. This review highlights the progress that is being made towards achieving potent inhibition of the EGFR-STAT3-Bcl-XL signaling axis in HNSCC and the promising therapeutic strategies that are currently under development for this disease.展开更多
基金supported by the Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine(No.ZYYCXTD-C-202208)2021 Shanghai Science and Technology Innovation Action Plan—Medical Innovation Research Project(No.31801153)the National Natural Youth Science Foundation of China(No.21MC1930500)。
文摘Objective:Gastric cancer(GC)is one of the most common malignancies seen in clinic and requires novel treatment options.Morin is a natural flavonoid extracted from the flower stalk of a highly valuable medicinal plant Prunella vulgaris L.,which exhibits an anti-cancer effect in multiple types of tumors.However,the therapeutic effect and underlying mechanism of morin in treating GC remains elusive.The study aims to explore the therapeutic effect and underlying molecular mechanisms of morin in GC.Methods:For in vitro experiments,the proliferation inhibition of morin was measured by cell counting kit-8 assay and colony formation assay in human GC cell line MKN45,human gastric adenocarcinoma cell line AGS,and human gastric epithelial cell line GES-1;for apoptosis analysis,microscopic photography,Western blotting,ubiquitination analysis,quantitative polymerase chain reaction analysis,flow cytometry,and RNA interference technology were employed.For in vivo studies,immunohistochemistry,biomedical analysis,and Western blotting were used to assess the efficacy and safety of morin in a xenograft mouse model of GC.Results:Morin significantly inhibited the proliferation of GC cells MKN45 and AGS in a dose-and timedependent manner,but did not inhibit human gastric epithelial cells GES-1.Only the caspase inhibitor Z-VAD-FMK was able to significantly reverse the inhibition of proliferation by morin in both GC cells,suggesting that apoptosis was the main type of cell death during the treatment.Morin induced intrinsic apoptosis in a dose-dependent manner in GC cells,which mainly relied on B cell leukemia/lymphoma 2(BCL-2)associated agonist of cell death(BAD)but not phorbol-12-myristate-13-acetate-induced protein 1.The upregulation of BAD by morin was due to blocking the ubiquitination degradation of BAD,rather than the transcription regulation and the phosphorylation of BAD.Furthermore,the combination of morin and BCL-2 inhibitor navitoclax(also known as ABT-737)produced a synergistic inhibitory effect in GC cells through amplifying apoptotic signals.In addition,morin treatment significantly suppressed the growth of GC in vivo by upregulating BAD and the subsequent activation of its downstream apoptosis pathway.Conclusion:Morin suppressed GC by inducing apoptosis,which was mainly due to blocking the ubiquitination-based degradation of the pro-apoptotic protein BAD.The combination of morin and the BCL-2 inhibitor ABT-737 synergistically amplified apoptotic signals in GC cells,which may overcome the drug resistance of the BCL-2 inhibitor.These findings indicated that morin was a potent and promising agent for GC treatment.
文摘The B-cell lymphoma-extra large （Bcl-xL） is a mitochondrial anti-apoptotic protein that plays a role in neuroprotection. However, during excitotoxic stimulation, Bcl-xL undergoes caspase-dependent cleavage and produces a fragmented form, △N-Bcl-xL. Accumulation of △N-Bcl-xL is associated with mitochon- drial dysfunction and neuronal death. Therefore, strategies to inhibit the activity or formation of △N-Bcl- xL protect the brain against excitotoxic injuries. Our team found that the pharmacological inhibitor △BT- 737 exerts dose dependent effects in primary neurons. When primary hippocampal neurons were treated with 1 μM ABT-737, glutamate-mediated mitochondrial damage and neuronal death were exacerbated, whereas 10 nM △BT-737, a 100-fold lower concentration, protected mitochondrial function and enhanced neuronal viability against glutamate toxicity. In addition, we suggested acute vs. prolonged formation of △N-Bcl-xL may have different effects on mitochondrial or neuronal functions. Unlike acute production of △N-Bcl-xL by glutamate, overexpression of △N-Bcl-xL did not cause drastic changes in neuronal viability. We predicted that neurons undergo adaptation and may activate altered metabolism to compensate for △N-Bcl-xL-mediated mitochondrial dysfunction. Although the detailed mechanism of ABT-mediated neurotoxicity neuroprotection is still unclear, our study shows that the mitochondrial membrane protein △N-Bcl-xL is a central target for interventions.
基金supported by National Institutes ofHealth grants R01 CA137260 and P50 CA097190
文摘Head and neck squamous cell carcinomas (HNSCC) are common human malignancies with poor clinical outcomes. The 5-year survival rates for patients with advanced stage HNSCC have not changed appreciably in the past few decades, underscoring a dire need for improved therapeutic options. Recent studies have elucidated a key signaling axis, the EGFR-STAT3-Bcl-XL signaling axis, that is aberrantly activated in a majority of HNSCC and contributes to the proliferation and survival of malignant cells. Considerable effort is being placed on developing highly specific inhibitors of different components of this pathway. This review highlights the progress that is being made towards achieving potent inhibition of the EGFR-STAT3-Bcl-XL signaling axis in HNSCC and the promising therapeutic strategies that are currently under development for this disease.
