CDK4/6 inhibitors are the standard treatment in advanced HR+/HER2-breast cancer patients.Nevertheless,the resistance to CDK4/6 inhibitors is inevitable and the strategies to overcome resistance are of great interest.H...CDK4/6 inhibitors are the standard treatment in advanced HR+/HER2-breast cancer patients.Nevertheless,the resistance to CDK4/6 inhibitors is inevitable and the strategies to overcome resistance are of great interest.Here,we show that the palbociclibresistant breast cancer cells expressed significantly higher levels of Cyclin D1 and CDK4 proteins because of upregulated protein synthesis.Silencing Cyclin D1 or CDK4 led to cell cycle arrest while silencing Cyclin E1 or CDK2 restored the sensitivity to palbociclib.Furthermore,PI3K/mTOR pathway was hyper-activated in palbociclib-resistant cells,leading to more phosphorylated 4E-BP1 and higher levels of Cyclin D1 and CDK4 translation.Targeting PI3K/mTOR pathway with a specific PI3Kαinhibitor(BYL719)or an mTOR inhibitor(everolimus)reduced the protein levels of Cyclin D1 and CDK4,and restored the sensitivity to palbociclib.The tumor samples expressed significantly higher levels of Cyclin D1,CDK4,p-AKT and p-4E-BP1 after progression on palbociclib treatment.In conclusion,our findings suggest that overexpressed Cyclin D1 and CDK4 proteins lead to the resistance to CDK4/6 inhibitor and PI3K/mTOR inhibitors are able to restore the sensitivity to CDK4/6 inhibitors,which provides the biomarker and rationale for the combinational use of CDK4/6 inhibitors and PI3K/mTOR inhibitors after CDK4/6 inhibitor resistance in breast cancer.展开更多
Tetra-bromo-methyl-resorcin[4]arene cavitands were synthesized and C-2 position amine functionalized to obtain C-propyl-o-toluidine-methyl-resorcin[4]arene cavitand 4, and the crystal containing one solvate molecule o...Tetra-bromo-methyl-resorcin[4]arene cavitands were synthesized and C-2 position amine functionalized to obtain C-propyl-o-toluidine-methyl-resorcin[4]arene cavitand 4, and the crystal containing one solvate molecule of ethanol was obtained in a dichloromethane-ethanol solvent system, its structure crystallized in the monoclinic space group P2<sub>1</sub>/n, with a = 12.521(3) Å, b = 21.738(6) Å, c = 25.353(6) Å, α = 90˚, β = 102.372(4)˚, γ = 90˚, and Z = 4. The compound was determined by single-crystal X-ray diffraction and characterized by <sup>1</sup>H NMR, FT-IR and elemental analyses.展开更多
LIN9 functions to regulate cell mitotic process.Dysregulation of LIN9 expression is associated with development of human cancers.In this study we assessed the association of LIN9 expression with paclitaxel resistance ...LIN9 functions to regulate cell mitotic process.Dysregulation of LIN9 expression is associated with development of human cancers.In this study we assessed the association of LIN9 expression with paclitaxel resistance and clarified the underlying mechanisms for the first time.LIN9 expression in breast cancer tissues was retrieved from publicly available online databases and statistically analyzed.Human TNBC cell lines MDA-MB-231 and MDA-MB-468 and their corresponding paclitaxelresistant sublines 231PTX and 468PTX were used to assess the expression of LIN9 by qRT-PCR and Western blot,cell growth by cell counting,cell viability by MTS assay,and cell apoptosis by flow cytometry.The data showed that high LIN9 expression in breast cancer patients receiving chemotherapy was related to poor overall survival(OS).LIN9 expression was upregulated in paclitaxel-resistant TNBC cells compared to their parental cells.Knockdown of LIN9 or treatment of paclitaxel-resistant TNBC cells with a bromo-and extra-terminal domain inhibitor(BETi)JQ1 which also decreased LIN9 expression enhanced the sensitivity of paclitaxel-resistant TNBC cells to paclitaxel.Mechanistically,decreased LIN9 in resistant cell lines reduced tumor cell viability,promoted multinucleated cells formation and induced tumor cell apoptosis,potentially by directly regulating microtubule-binding protein CCSAP.In conclusion,high LIN9 expression contributed to poor clinical outcomes and paclitaxel resistance in TNBC and BETi,targeting LIN9 expression,could be a reversible drug for PTX-resistant TNBC patients.展开更多
Studies on influenza virus by Chinese Academy of Sciences(CAS)could be traced back as early as 2005 by the CAS Key Laboratory of Pathogenic Microbiology and Immunology(CASPMI),who discovered that Qinghai-like Clade 2....Studies on influenza virus by Chinese Academy of Sciences(CAS)could be traced back as early as 2005 by the CAS Key Laboratory of Pathogenic Microbiology and Immunology(CASPMI),who discovered that Qinghai-like Clade 2.2H5N1 subtype highly pathogenic avian influenza virus(HPAIV)first caused severe outbreak in wild birds in Qinghai Lake(Liu et al.,2005).展开更多
基金supported by the Notional Natural Science Foundation of China(82061148016,81630074,81872141,81702630,81672622)Guangzhou Science and Technology Plan Key Projects(201804020076)+2 种基金Natural Science Foundation of Guangdong(2019A1515010146)Beijing Medical Award Foundation(YXJL-20200941-0760)China Postdoctoral Science Foundation(2021TQ0384,2021M703731)。
文摘CDK4/6 inhibitors are the standard treatment in advanced HR+/HER2-breast cancer patients.Nevertheless,the resistance to CDK4/6 inhibitors is inevitable and the strategies to overcome resistance are of great interest.Here,we show that the palbociclibresistant breast cancer cells expressed significantly higher levels of Cyclin D1 and CDK4 proteins because of upregulated protein synthesis.Silencing Cyclin D1 or CDK4 led to cell cycle arrest while silencing Cyclin E1 or CDK2 restored the sensitivity to palbociclib.Furthermore,PI3K/mTOR pathway was hyper-activated in palbociclib-resistant cells,leading to more phosphorylated 4E-BP1 and higher levels of Cyclin D1 and CDK4 translation.Targeting PI3K/mTOR pathway with a specific PI3Kαinhibitor(BYL719)or an mTOR inhibitor(everolimus)reduced the protein levels of Cyclin D1 and CDK4,and restored the sensitivity to palbociclib.The tumor samples expressed significantly higher levels of Cyclin D1,CDK4,p-AKT and p-4E-BP1 after progression on palbociclib treatment.In conclusion,our findings suggest that overexpressed Cyclin D1 and CDK4 proteins lead to the resistance to CDK4/6 inhibitor and PI3K/mTOR inhibitors are able to restore the sensitivity to CDK4/6 inhibitors,which provides the biomarker and rationale for the combinational use of CDK4/6 inhibitors and PI3K/mTOR inhibitors after CDK4/6 inhibitor resistance in breast cancer.
文摘Tetra-bromo-methyl-resorcin[4]arene cavitands were synthesized and C-2 position amine functionalized to obtain C-propyl-o-toluidine-methyl-resorcin[4]arene cavitand 4, and the crystal containing one solvate molecule of ethanol was obtained in a dichloromethane-ethanol solvent system, its structure crystallized in the monoclinic space group P2<sub>1</sub>/n, with a = 12.521(3) Å, b = 21.738(6) Å, c = 25.353(6) Å, α = 90˚, β = 102.372(4)˚, γ = 90˚, and Z = 4. The compound was determined by single-crystal X-ray diffraction and characterized by <sup>1</sup>H NMR, FT-IR and elemental analyses.
基金This work was supported by the National Natural Science Foundation of China(81672622,81702630)China Postdoctoral Science Foundation(2018M643331).
文摘LIN9 functions to regulate cell mitotic process.Dysregulation of LIN9 expression is associated with development of human cancers.In this study we assessed the association of LIN9 expression with paclitaxel resistance and clarified the underlying mechanisms for the first time.LIN9 expression in breast cancer tissues was retrieved from publicly available online databases and statistically analyzed.Human TNBC cell lines MDA-MB-231 and MDA-MB-468 and their corresponding paclitaxelresistant sublines 231PTX and 468PTX were used to assess the expression of LIN9 by qRT-PCR and Western blot,cell growth by cell counting,cell viability by MTS assay,and cell apoptosis by flow cytometry.The data showed that high LIN9 expression in breast cancer patients receiving chemotherapy was related to poor overall survival(OS).LIN9 expression was upregulated in paclitaxel-resistant TNBC cells compared to their parental cells.Knockdown of LIN9 or treatment of paclitaxel-resistant TNBC cells with a bromo-and extra-terminal domain inhibitor(BETi)JQ1 which also decreased LIN9 expression enhanced the sensitivity of paclitaxel-resistant TNBC cells to paclitaxel.Mechanistically,decreased LIN9 in resistant cell lines reduced tumor cell viability,promoted multinucleated cells formation and induced tumor cell apoptosis,potentially by directly regulating microtubule-binding protein CCSAP.In conclusion,high LIN9 expression contributed to poor clinical outcomes and paclitaxel resistance in TNBC and BETi,targeting LIN9 expression,could be a reversible drug for PTX-resistant TNBC patients.
基金supported by the National Key R&D Program of China(2016YFE0205800)National Science and Technology Major Project(2016ZX10004222)+5 种基金Emergency Technology Research Issue on Prevention and Control for Human Infection with A(H7N9)Avian Influenza Virus(10600100000015001206)intramural special grants for influenza virus research from the Chinese Academy of Sciences(KJZD-EWL15)Tianjin Research Program of the Application Foundation and Advanced Technology(14JCYBJC24400)the research project RFBR 17-04-01919a leading principal investigator of the NSFC Innovative Research Group(81621091)supported by the Youth Innovation Promotion Association of Chinese Academy of Sciences(CAS)(2017122)
文摘Studies on influenza virus by Chinese Academy of Sciences(CAS)could be traced back as early as 2005 by the CAS Key Laboratory of Pathogenic Microbiology and Immunology(CASPMI),who discovered that Qinghai-like Clade 2.2H5N1 subtype highly pathogenic avian influenza virus(HPAIV)first caused severe outbreak in wild birds in Qinghai Lake(Liu et al.,2005).
