Lung cancer is the leading cause of cancer related death in the United States killing over 130,000 people each year. While a combination of chemo and radiation therapy may be effective, surgery is still required for m...Lung cancer is the leading cause of cancer related death in the United States killing over 130,000 people each year. While a combination of chemo and radiation therapy may be effective, surgery is still required for many patients. Without surgery, the disease may progress and lead to metastases. We sought to determine if treatment with anti-non-muscle myosin IIA antibody would inhibit movement of the cells in the presence and absence of glabridin (an isoflavonoid compound shown to inhibit cell migration by inhibiting myosin). We compared inhibition by glabridin to that of an anti-non-muscle myosin IIA antibody and a combination therapy of both at 12 and 24 hours post wound creation. Cells that took up the anti-non-muscle myosin IIA antibody were greatly inhibited in motility and exhibited no significant change in wound healing. Glabridin treatment resulted in a dramatic increase in wound size within 12 hours and regeneration within 24 hours. The greatest decrease in motility was observed in cells treated with the combination of both glabridin and anti-non-muscle myosin IIA antibody. By 24 hrs, cell migration had halted due to death of the cells resulting from this combination. Further testing needs to be done to determine a safe mode of delivery of the combination therapy to ensure only local distribution. Controlled release drug delivery depot systems have been used as a means to provide local release of drugs intra-tumorally or adjacent to the cancerous tissue after surgical resection and have great potential.展开更多
Tumor metastasis depends on the dynamic balance of the actomyosin cytoskeleton.As a key component of actomyosin filaments,non-muscle myosin-ⅡA disassembly contributes to tumor cell spreading and migration.However,its...Tumor metastasis depends on the dynamic balance of the actomyosin cytoskeleton.As a key component of actomyosin filaments,non-muscle myosin-ⅡA disassembly contributes to tumor cell spreading and migration.However,its regulatory mechanism in tumor migration and invasion is poorly understood.Here,we found that oncoprotein hepatitis B X-interacting protein(HBXIP) blocked the myosin-ⅡA assemble state promoting breast cancer cell migration.Mechanistically,mass spectrometry analysis,co-immunoprecipitation assay and GST-pull down assay proved that HBXIP directly interacted with the assembly-competent domain(ACD) of non-muscle heavy chain myosin-ⅡA(NMHC-ⅡA).The interaction was enhanced by NMHC-ⅡA S1916 phosphorylation via HBXIP-recruited protein kinase PKCβⅡ.Moreover,HBXIP induced the transcription of PRKCB,encoding PKCβⅡ,by coactivating Sp1,and triggered PKCβⅡ kinase activity.Interestingly,RNA sequencing and mouse metastasis model indicated that the anti-hyperlipidemic drug bezafibrate(BZF) suppressed breast cancer metastasis via inhibiting PKCβⅡ-mediated NMHC-ⅡA phosphorylation in vitro and in vivo.We reveal a novel mechanism by which HBXIP promotes myosin-ⅡA disassembly via interacting and phosphorylating NMHC-ⅡA,and BZF can serve as an effective anti-metastatic drug in breast cancer.展开更多
文摘Lung cancer is the leading cause of cancer related death in the United States killing over 130,000 people each year. While a combination of chemo and radiation therapy may be effective, surgery is still required for many patients. Without surgery, the disease may progress and lead to metastases. We sought to determine if treatment with anti-non-muscle myosin IIA antibody would inhibit movement of the cells in the presence and absence of glabridin (an isoflavonoid compound shown to inhibit cell migration by inhibiting myosin). We compared inhibition by glabridin to that of an anti-non-muscle myosin IIA antibody and a combination therapy of both at 12 and 24 hours post wound creation. Cells that took up the anti-non-muscle myosin IIA antibody were greatly inhibited in motility and exhibited no significant change in wound healing. Glabridin treatment resulted in a dramatic increase in wound size within 12 hours and regeneration within 24 hours. The greatest decrease in motility was observed in cells treated with the combination of both glabridin and anti-non-muscle myosin IIA antibody. By 24 hrs, cell migration had halted due to death of the cells resulting from this combination. Further testing needs to be done to determine a safe mode of delivery of the combination therapy to ensure only local distribution. Controlled release drug delivery depot systems have been used as a means to provide local release of drugs intra-tumorally or adjacent to the cancerous tissue after surgical resection and have great potential.
基金supported by the grants from National Natural Science Foundation of China(82072929,82072943,and 31870752,China).
文摘Tumor metastasis depends on the dynamic balance of the actomyosin cytoskeleton.As a key component of actomyosin filaments,non-muscle myosin-ⅡA disassembly contributes to tumor cell spreading and migration.However,its regulatory mechanism in tumor migration and invasion is poorly understood.Here,we found that oncoprotein hepatitis B X-interacting protein(HBXIP) blocked the myosin-ⅡA assemble state promoting breast cancer cell migration.Mechanistically,mass spectrometry analysis,co-immunoprecipitation assay and GST-pull down assay proved that HBXIP directly interacted with the assembly-competent domain(ACD) of non-muscle heavy chain myosin-ⅡA(NMHC-ⅡA).The interaction was enhanced by NMHC-ⅡA S1916 phosphorylation via HBXIP-recruited protein kinase PKCβⅡ.Moreover,HBXIP induced the transcription of PRKCB,encoding PKCβⅡ,by coactivating Sp1,and triggered PKCβⅡ kinase activity.Interestingly,RNA sequencing and mouse metastasis model indicated that the anti-hyperlipidemic drug bezafibrate(BZF) suppressed breast cancer metastasis via inhibiting PKCβⅡ-mediated NMHC-ⅡA phosphorylation in vitro and in vivo.We reveal a novel mechanism by which HBXIP promotes myosin-ⅡA disassembly via interacting and phosphorylating NMHC-ⅡA,and BZF can serve as an effective anti-metastatic drug in breast cancer.
