The evasion from controlled cell death induction has been considered as one of the hallmarks of cancer cells. Defects in cell death signaling are a fundamental phenomenon in colorectal cancer. Nearly any non-invasive ...The evasion from controlled cell death induction has been considered as one of the hallmarks of cancer cells. Defects in cell death signaling are a fundamental phenomenon in colorectal cancer. Nearly any non-invasive cancer treatment finally aims to induce cell death. However, apoptosis resistance is the major cause for insufficient therapeutic success and disease relapse in gastrointestinal oncology. Various compounds have been developed and evaluated with the aim to meet with this obstacle by triggering cell death in cancer cells. The aim of this review is to illustrate current approaches and future directions in targeting cell death signaling in colorectal cancer. The complex signaling network of apoptosis will be demonstrated and the “druggability” of targets will be identified. In detail, proteins regulating mitochondrial cell death in colorectal cancer, such as Bcl-2 and survivin, will be discussed with respect to potential therapeutic exploitation. Death receptor signaling and targeting in colorectal cancer will be outlined. Encouraging clinical trials including cell death based targeted therapies for colorectal cancer are under way and will be demonstrated. Our conceptual understanding of cell death in cancer is rapidly emerging and new types of controlled cellular death have been identified. To meet this progress in cell death research, the implication of autophagy and necroptosis for colorectal carcinogenesis and therapeutic approaches will also be depicted. The main focus of this topic highlight will be on the revelation of the complex cell death concepts in colorectal cancer and the bridging from basic research to clinical use.展开更多
Objective:To explore the molecular mechanism by which cordycepin inhibits cell proliferation and induces apoptosis of human colorectal cancer cells.Methods:Cell counting and MTS(3-(4,5-dimethylthiazol-2-yl)-5-(3-carbo...Objective:To explore the molecular mechanism by which cordycepin inhibits cell proliferation and induces apoptosis of human colorectal cancer cells.Methods:Cell counting and MTS(3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfopheny)-2H-tetrazolium,inner salt) method were used to monitor the effects of cordycepin on cell proliferation.Flow cytometry(FCM) was used to analyze the effects of cordycepin on the cell cycle progress.Annexin V-fluorescein isothiocyanate(FITC) analysis was used to detect apoptosis at a very early stage.Caspase-Glo was used to determine caspase activity and Western blot was used to measure protein expression levels of c-Jun N-terminal kinase(JNK),p38,and Bcl-2 pro-apoptosis family.Results:The numbers of viable SW480 and SW620 cells and the proliferation of these cells were significantly reduced with increases in cordycepin concentration(P<0.01).The cell cycle progression of SW480 and SW620 was arrested at the G0/G1 phase by the addition of cordycepin,and apoptosis rates of cordycepin treatments were increased compared with the control group.Cordycepin-treated cells showed phosphatidylserine valgus,suggesting the existence of early apoptosis.Caspase-3/7 and-9 activity significantly increased and the protein expression levels of JNK,p38,and Bax,Bid,Bim,and Puma from Bcl-2 pro-apoptosis molecules also increased after the treatment with cordycepin.Conclusions:Cordycepin can inhibit SW480 and SW620 cell proliferation and induce apoptosis.Apoptosis might be induced by enhancing JNK and p38 kinase activity and increasing the protein expression of Bcl-2 pro-apoptotic molecules.展开更多
The majority of colorectal cancer patients are not responsive to immune checkpoint blockade(ICB).The interferon gamma(IFNγ)signaling pathway drives spontaneous and ICB-induced antitumor immunity.In this review,we sum...The majority of colorectal cancer patients are not responsive to immune checkpoint blockade(ICB).The interferon gamma(IFNγ)signaling pathway drives spontaneous and ICB-induced antitumor immunity.In this review,we summarize recent advances in the epigenetic,genetic,and functional integrity of the IFNγsignaling pathway in the colorectal cancer microenvironment and its immunological relevance in the therapeutic efficacy of and resistance to ICB.Moreover,we discuss how to target IFNγsignaling to inform novel clinical trials to treat patients with colorectal cancer.展开更多
基金BCK holds a Postdoctoral-Fellowship from the Medical Faculty of the University of Heidelberg,GermanyHSB receives grants from the German Research Foundation (DFG SCHU 1443/4-1)
文摘The evasion from controlled cell death induction has been considered as one of the hallmarks of cancer cells. Defects in cell death signaling are a fundamental phenomenon in colorectal cancer. Nearly any non-invasive cancer treatment finally aims to induce cell death. However, apoptosis resistance is the major cause for insufficient therapeutic success and disease relapse in gastrointestinal oncology. Various compounds have been developed and evaluated with the aim to meet with this obstacle by triggering cell death in cancer cells. The aim of this review is to illustrate current approaches and future directions in targeting cell death signaling in colorectal cancer. The complex signaling network of apoptosis will be demonstrated and the “druggability” of targets will be identified. In detail, proteins regulating mitochondrial cell death in colorectal cancer, such as Bcl-2 and survivin, will be discussed with respect to potential therapeutic exploitation. Death receptor signaling and targeting in colorectal cancer will be outlined. Encouraging clinical trials including cell death based targeted therapies for colorectal cancer are under way and will be demonstrated. Our conceptual understanding of cell death in cancer is rapidly emerging and new types of controlled cellular death have been identified. To meet this progress in cell death research, the implication of autophagy and necroptosis for colorectal carcinogenesis and therapeutic approaches will also be depicted. The main focus of this topic highlight will be on the revelation of the complex cell death concepts in colorectal cancer and the bridging from basic research to clinical use.
基金supported by the Department of Education of Zhejiang Province(No. Y200804636)the Department of Science and Tech-nology of Zhejiang Province(Nos. 2008C23049,2007C23027,and2009C33081)the Natural Science Foundation of Zhejiang Province(No. Y206174),China
文摘Objective:To explore the molecular mechanism by which cordycepin inhibits cell proliferation and induces apoptosis of human colorectal cancer cells.Methods:Cell counting and MTS(3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfopheny)-2H-tetrazolium,inner salt) method were used to monitor the effects of cordycepin on cell proliferation.Flow cytometry(FCM) was used to analyze the effects of cordycepin on the cell cycle progress.Annexin V-fluorescein isothiocyanate(FITC) analysis was used to detect apoptosis at a very early stage.Caspase-Glo was used to determine caspase activity and Western blot was used to measure protein expression levels of c-Jun N-terminal kinase(JNK),p38,and Bcl-2 pro-apoptosis family.Results:The numbers of viable SW480 and SW620 cells and the proliferation of these cells were significantly reduced with increases in cordycepin concentration(P<0.01).The cell cycle progression of SW480 and SW620 was arrested at the G0/G1 phase by the addition of cordycepin,and apoptosis rates of cordycepin treatments were increased compared with the control group.Cordycepin-treated cells showed phosphatidylserine valgus,suggesting the existence of early apoptosis.Caspase-3/7 and-9 activity significantly increased and the protein expression levels of JNK,p38,and Bax,Bid,Bim,and Puma from Bcl-2 pro-apoptosis molecules also increased after the treatment with cordycepin.Conclusions:Cordycepin can inhibit SW480 and SW620 cell proliferation and induce apoptosis.Apoptosis might be induced by enhancing JNK and p38 kinase activity and increasing the protein expression of Bcl-2 pro-apoptotic molecules.
基金This work was supported in part by U.S.NIH/NCI R01 grants(CA217648,CA123088,CA099985,CA193136,CA152470)the NIH through the University of Michigan Rogel Cancer Center Grant(CA46592).
文摘The majority of colorectal cancer patients are not responsive to immune checkpoint blockade(ICB).The interferon gamma(IFNγ)signaling pathway drives spontaneous and ICB-induced antitumor immunity.In this review,we summarize recent advances in the epigenetic,genetic,and functional integrity of the IFNγsignaling pathway in the colorectal cancer microenvironment and its immunological relevance in the therapeutic efficacy of and resistance to ICB.Moreover,we discuss how to target IFNγsignaling to inform novel clinical trials to treat patients with colorectal cancer.
