Advanced prostate cancer is treated with androgen deprivation, but most patients eventually progress and need new therapy. Recent genomic/exomic sequencing identified SPOP as the most frequently mutated gene in 6% - 1...Advanced prostate cancer is treated with androgen deprivation, but most patients eventually progress and need new therapy. Recent genomic/exomic sequencing identified SPOP as the most frequently mutated gene in 6% - 15% of prostate cancer. Based on the function of SPOP as a ubiquitin ligase in protein degradation, it was hypothesized that loss-of-function mutations of SPOP led to accumulation of SPOP substrates that enhance androgen receptor activity and facilitate prostate cancer formation. SPOP substrates could thus be potential targets for treatment of androgen-sensitive prostate cancer. PubMed and BLAST search identified that Gli, SRC-3, and AWP1 are SPOP substrates, and that inhibition of PRK-1, a binding partner of AWP1, by lestaurtinib suppressed androgen receptor activity. LNCaP, PC3, DU145 and 22RV1 prostate cancer cells were used to evaluate the effect of lestaurtinib. LNCaP cells, an androgen-sensitive prostate cancer cell line, were the most sensitive. SRC-3 protein decreased when LNCaP cells were treated with lestaurtinib;whereas PRK-1 increased in nucleus after lestaurtinib treatment. These data suggest that lestaurtinib modulates SRC-3 and PRK-1 to induced cell death in androgen-sensitive prostate cancer, and could be a useful agent for future development for prostate cancer with SPOP mutations.展开更多
Objective： To investigate the effects of gambogic acid （GA） on the proliferation and apoptosis of Human lung adenocarcinoma A549 cells in vitro, as well as the regulation of steroid receptor coactivator-3 （SRC-3）...Objective： To investigate the effects of gambogic acid （GA） on the proliferation and apoptosis of Human lung adenocarcinoma A549 cells in vitro, as well as the regulation of steroid receptor coactivator-3 （SRC-3） to explore the relationship between them. Methods： The effect of GA on the growth of A549 cells was studied by MTT assay. Apoptosis was detected through Hoechst 33258 staining. RT-PCR and Western blot technologies were applied to assess the expression of SRC-3, whereas, the localization of SRC-3 was determined by using confocal microscopy method. Results： GA presented striking proliferation inhibition potency on A549 cells in vitro in a time- and dose-dependent manner, with the IC50 value for 24 h was 3.17±0.13 μmol/L. Hoechst 33258 staining showed that GA could induce apoptosis in A549 cells. Over-expression of SRC-3 was found in A549 cells, whereas the mRNA and protein expression levels of SRC-3 were significantly downregulated in A549 cells induced by GA in a dose-dependent manner. The disposition of SRC-3 was situated mainly at the nuclear. Conclusion： GA may exert its strong anti-leukemia effects through the regulation of the expression of SRC-3. It may be a new target for the therapy of lung cancer.展开更多
To complete their life cycle and spread, viruses interfere with and gain control of diverse cellular processes, this most often occurring through interaction between viral proteins(VPs) and resident protein partners. ...To complete their life cycle and spread, viruses interfere with and gain control of diverse cellular processes, this most often occurring through interaction between viral proteins(VPs) and resident protein partners. Among the latter, Src family kinases(SFKs), a class of non-receptor tyrosine kinases that contributes to the conversion of extracellular signals into intracellular signaling cascades and is involved in virtually all cellular processes, have recently emerged as critical mediators between the cell's infrastructure and the viral demands. In this scenario, structural or ex novo synthesized VPs are able to bind to the different domains of these enzymes through specific short linear motifs present along their sequences. Proline-rich motifs displaying the conserved minimal consensus PxxP and recognizing the SFK Src homology(SH)3 domain constitute a cardinal signature for the formation of multiprotein complexes and this interaction may promote phosphorylation of VPs by SFKs, thus creating phosphotyrosine motifs that become a docking site for the SH2 domains of SFKs or other SH2 domain-bearing signaling molecules. Importantly, the formation of these assemblies also results in a change in the activity and/or location of SFKs, and these events are critical in perturbing key signalingpathways so that viruses can utilize the cell's machinery to their own benefit. In the light of these observations, although VPs as such, especially those with enzyme activity, are still regarded as valuable targets for therapeutic strategies, multiprotein complexes composed of viral and host cell proteins are increasingly becoming objects of investigation with a view to deeply characterize the structural aspects that favor their formation and to develop new compounds able to contrast viral diseases in an alternative manner.展开更多
文摘Advanced prostate cancer is treated with androgen deprivation, but most patients eventually progress and need new therapy. Recent genomic/exomic sequencing identified SPOP as the most frequently mutated gene in 6% - 15% of prostate cancer. Based on the function of SPOP as a ubiquitin ligase in protein degradation, it was hypothesized that loss-of-function mutations of SPOP led to accumulation of SPOP substrates that enhance androgen receptor activity and facilitate prostate cancer formation. SPOP substrates could thus be potential targets for treatment of androgen-sensitive prostate cancer. PubMed and BLAST search identified that Gli, SRC-3, and AWP1 are SPOP substrates, and that inhibition of PRK-1, a binding partner of AWP1, by lestaurtinib suppressed androgen receptor activity. LNCaP, PC3, DU145 and 22RV1 prostate cancer cells were used to evaluate the effect of lestaurtinib. LNCaP cells, an androgen-sensitive prostate cancer cell line, were the most sensitive. SRC-3 protein decreased when LNCaP cells were treated with lestaurtinib;whereas PRK-1 increased in nucleus after lestaurtinib treatment. These data suggest that lestaurtinib modulates SRC-3 and PRK-1 to induced cell death in androgen-sensitive prostate cancer, and could be a useful agent for future development for prostate cancer with SPOP mutations.
基金supported by the National Natural Science Foundation of China (No. 30472267).
文摘Objective： To investigate the effects of gambogic acid （GA） on the proliferation and apoptosis of Human lung adenocarcinoma A549 cells in vitro, as well as the regulation of steroid receptor coactivator-3 （SRC-3） to explore the relationship between them. Methods： The effect of GA on the growth of A549 cells was studied by MTT assay. Apoptosis was detected through Hoechst 33258 staining. RT-PCR and Western blot technologies were applied to assess the expression of SRC-3, whereas, the localization of SRC-3 was determined by using confocal microscopy method. Results： GA presented striking proliferation inhibition potency on A549 cells in vitro in a time- and dose-dependent manner, with the IC50 value for 24 h was 3.17±0.13 μmol/L. Hoechst 33258 staining showed that GA could induce apoptosis in A549 cells. Over-expression of SRC-3 was found in A549 cells, whereas the mRNA and protein expression levels of SRC-3 were significantly downregulated in A549 cells induced by GA in a dose-dependent manner. The disposition of SRC-3 was situated mainly at the nuclear. Conclusion： GA may exert its strong anti-leukemia effects through the regulation of the expression of SRC-3. It may be a new target for the therapy of lung cancer.
文摘To complete their life cycle and spread, viruses interfere with and gain control of diverse cellular processes, this most often occurring through interaction between viral proteins(VPs) and resident protein partners. Among the latter, Src family kinases(SFKs), a class of non-receptor tyrosine kinases that contributes to the conversion of extracellular signals into intracellular signaling cascades and is involved in virtually all cellular processes, have recently emerged as critical mediators between the cell's infrastructure and the viral demands. In this scenario, structural or ex novo synthesized VPs are able to bind to the different domains of these enzymes through specific short linear motifs present along their sequences. Proline-rich motifs displaying the conserved minimal consensus PxxP and recognizing the SFK Src homology(SH)3 domain constitute a cardinal signature for the formation of multiprotein complexes and this interaction may promote phosphorylation of VPs by SFKs, thus creating phosphotyrosine motifs that become a docking site for the SH2 domains of SFKs or other SH2 domain-bearing signaling molecules. Importantly, the formation of these assemblies also results in a change in the activity and/or location of SFKs, and these events are critical in perturbing key signalingpathways so that viruses can utilize the cell's machinery to their own benefit. In the light of these observations, although VPs as such, especially those with enzyme activity, are still regarded as valuable targets for therapeutic strategies, multiprotein complexes composed of viral and host cell proteins are increasingly becoming objects of investigation with a view to deeply characterize the structural aspects that favor their formation and to develop new compounds able to contrast viral diseases in an alternative manner.
