Background:Picropodophllotoxin(PPT),a principal component of Podophyllum hexandrum root,demonstrates various beneficial biological activities in multiple cancer types,including antitumor and antiproliferative properti...Background:Picropodophllotoxin(PPT),a principal component of Podophyllum hexandrum root,demonstrates various beneficial biological activities in multiple cancer types,including antitumor and antiproliferative properties.Despite its known effects,the specific mechanisms by which PPT induces apoptosis in oral squamous cell carcinoma(OSCC)cells lack full clarification.Aims:This study aimed to evaluate the role of PPT in inducing apoptosis in OSCC cells by targeting signal transducer and activator of transcription 3(STAT3)and to investigate the underlying molecular pathways.Methods:Human OSCC cell lines(HN22 and HSC4)were treated with PPT.Cell viability,colony formation,and apoptotic morphological changes were evaluated.Reactive oxygen species(ROS)generation and mitochondrial function were assessed using tetramethyl rhodamine methyl ester,MitoSOX,and 2′,7′-dichlorodihydrofluorescein diacetate(DCFH-DA)assays following PPT treatment.The expression of apoptosis markers,including cleaved Poly(ADP-Ribose)Polymerase(c-PARP)and other target proteins,was measured using western blotting.ROS involvement was further confirmed using the ROS scavenger N-acetylcysteine(NAC).Results:Treatment with PPT resulted in a substantial reduction in cell viability,a decrease in colony formation capacity,and evident morphological changes in OSCC cells.These effects were dose-and time-dependent,as evidenced by increased expression of c-PARP.PPT-induced apoptosis was mediated by excessive ROS generation,which was almost completely blocked by NAC pretreatment.Conclusions:These findings suggest that PPT may serve as a promising therapeutic agent for treating human oral cancer by inhibiting the STAT3 pathway and inducing ROS-mediated apoptosis.展开更多
Reactive oxygen species(ROS)are believed to be inevitable and toxic by-products produced during cellular respiration.However,several lines of evidence show that diverse extracellular signals can activate ROS productio...Reactive oxygen species(ROS)are believed to be inevitable and toxic by-products produced during cellular respiration.However,several lines of evidence show that diverse extracellular signals can activate ROS production and provide important function for various biological processes.展开更多
Increased expression levels of the RNA splicing regulator Transformer2fl （abbreviated Tra2fl） have been reported in several types of cancer. Recent work has revealed an intimate cross-regulation between Tra2fl and t...Increased expression levels of the RNA splicing regulator Transformer2fl （abbreviated Tra2fl） have been reported in several types of cancer. Recent work has revealed an intimate cross-regulation between Tra2fl and the highly similar Tra2a protein in human breast cancer cells, though these two proteins are encoded by separate genes created by a gene duplication that occurred over 500 million years ago. This cross-regulation involves splicing control of a special class of exons, called poison exons. Down-regulation of Tra2fl reduces splicing inclu- sion of a poison exon in the mRNA encoding Tra2a, thereby up-regulating Tra2a protein expression. This buffers any splicing changes that might be caused by individual depletion of Tra2fl alone. Discovery of this cross-regulation pathway, and its by-pass by joint deple- tion of both human Tra2 proteins, revealed Tra2 proteins are essential for breast cancer cell viability, and led to the identification of important targets for splicing control. These exons include a critical exon within the checkpoint kinase 1 （CHK1） gene that plays a crucial function in the protection of cancer cells from replication stress. Breast cancer cells depleted for Tra2 proteins have reduced CHK1 protein levels and accumulate DNA damage. These data suggest Tra2 proteins and/or their splicing targets as possible cancer drug targets.展开更多
基金supported by the Korea Institute of Toxicology(KIT)Research Program[No.2710008763(KK-2401-01)]the Korea Environmental Industry&Technology Institute(KEITI)through the Core Technology Development Project for Environmental Diseases Prevention and Management[No.2480000072(RS-2021-KE001705)]。
文摘Background:Picropodophllotoxin(PPT),a principal component of Podophyllum hexandrum root,demonstrates various beneficial biological activities in multiple cancer types,including antitumor and antiproliferative properties.Despite its known effects,the specific mechanisms by which PPT induces apoptosis in oral squamous cell carcinoma(OSCC)cells lack full clarification.Aims:This study aimed to evaluate the role of PPT in inducing apoptosis in OSCC cells by targeting signal transducer and activator of transcription 3(STAT3)and to investigate the underlying molecular pathways.Methods:Human OSCC cell lines(HN22 and HSC4)were treated with PPT.Cell viability,colony formation,and apoptotic morphological changes were evaluated.Reactive oxygen species(ROS)generation and mitochondrial function were assessed using tetramethyl rhodamine methyl ester,MitoSOX,and 2′,7′-dichlorodihydrofluorescein diacetate(DCFH-DA)assays following PPT treatment.The expression of apoptosis markers,including cleaved Poly(ADP-Ribose)Polymerase(c-PARP)and other target proteins,was measured using western blotting.ROS involvement was further confirmed using the ROS scavenger N-acetylcysteine(NAC).Results:Treatment with PPT resulted in a substantial reduction in cell viability,a decrease in colony formation capacity,and evident morphological changes in OSCC cells.These effects were dose-and time-dependent,as evidenced by increased expression of c-PARP.PPT-induced apoptosis was mediated by excessive ROS generation,which was almost completely blocked by NAC pretreatment.Conclusions:These findings suggest that PPT may serve as a promising therapeutic agent for treating human oral cancer by inhibiting the STAT3 pathway and inducing ROS-mediated apoptosis.
基金supported by grants from the Korean Ministry of Trade,Industry and Energy(10063396)the National Research Foundation(NRF)of Korea(2018M3A9B8021980)
文摘Reactive oxygen species(ROS)are believed to be inevitable and toxic by-products produced during cellular respiration.However,several lines of evidence show that diverse extracellular signals can activate ROS production and provide important function for various biological processes.
文摘Increased expression levels of the RNA splicing regulator Transformer2fl （abbreviated Tra2fl） have been reported in several types of cancer. Recent work has revealed an intimate cross-regulation between Tra2fl and the highly similar Tra2a protein in human breast cancer cells, though these two proteins are encoded by separate genes created by a gene duplication that occurred over 500 million years ago. This cross-regulation involves splicing control of a special class of exons, called poison exons. Down-regulation of Tra2fl reduces splicing inclu- sion of a poison exon in the mRNA encoding Tra2a, thereby up-regulating Tra2a protein expression. This buffers any splicing changes that might be caused by individual depletion of Tra2fl alone. Discovery of this cross-regulation pathway, and its by-pass by joint deple- tion of both human Tra2 proteins, revealed Tra2 proteins are essential for breast cancer cell viability, and led to the identification of important targets for splicing control. These exons include a critical exon within the checkpoint kinase 1 （CHK1） gene that plays a crucial function in the protection of cancer cells from replication stress. Breast cancer cells depleted for Tra2 proteins have reduced CHK1 protein levels and accumulate DNA damage. These data suggest Tra2 proteins and/or their splicing targets as possible cancer drug targets.
