Market drugs,suchas Foodand Drug Administration(FDA)or European Medicines Agency(EMA)-approved drugs for specific indications provide opportunities for repurposing for newer therapeutics.This potentially saves resourc...Market drugs,suchas Foodand Drug Administration(FDA)or European Medicines Agency(EMA)-approved drugs for specific indications provide opportunities for repurposing for newer therapeutics.This potentially saves resources invested in clinical trials that verify drug safety and tolerance in humans prior to alternative indication approval.Protein arginine methyltransferase 5(PRMT5)overexpression has been linked to promoting the tumor phenotype in several cancers,including pancreatic ductal adenocarcinoma(PDAC),colorectal cancer(CRC),and breast cancer(BC),making PRMT5 an important target for cancer therapy.Previously,we showed that PRMT5-mediated methylation of the nuclear factor(NF)-kB,partially contributes to its constitutive activation observed in cancers.In this study,we utilized an AlphaLiSA-based high-throughput screening method adapted in our lab,and identified one FDA-approved drug,Candesartan cilexetil(Can,used in hypertension treatment)and one EMA-approved drug,Cloperastine hydrochloride(Clo,used in cough treatment)that had significant PRMT5-inhibitory activity,and their anti-tumor properties were validated using cancer phenotypic assays in vitro.Furthermore,PRMT5 selective inhibition of methyltransferase activity was confirmed by reduction of both NF-kB methylation and its subsequent activation upon drug treatment.Using in silico prediction,we identified critical residues on PRMT5 targeted by these drugs that may interfere with its enzymatic activity.Finally,Clo and Can treatment have exhibited marked reduction in tumor growth in vivo.Overall,we provide basis for pursuing repurposing Clo and Can as anti-PRMT5 cancer therapies.Our study offers potential safe and fast repurposing of previously unknown PRMT5 inhibitors into clinical practice.展开更多
Y box binding protein-1(YBX1)belongs to a DNA-and RNA-binding family of transcription factors,containing the highly conserved cold shock domain(CSD).YBX1 is involved in a number of cellular functions including transcr...Y box binding protein-1(YBX1)belongs to a DNA-and RNA-binding family of transcription factors,containing the highly conserved cold shock domain(CSD).YBX1 is involved in a number of cellular functions including transcription,translation,DNA damage repair etc.,and it is upregulated during times of environmental stress.YBX1 is localized in both the cytoplasm and the nucleus.There,its nuclear translocation is observed in a number of cancers and is associated with poor prognosis and disease progression.Additionally,YBX1 expression is upregulated in a variety of cancers,pointing towards its role as a potential oncogene.Under certain circumstances,YBX1 also promotes the expression of multidrug resistance 1(MDR1)gene,which is involved in the development of drug resistance.Thus,it is critical to understand the mechanism of YBX1 regulation and its downstream effects on promoting cancer development.A number of recent studies have highlighted the mechanisms of YBX1 regulation.Mass spectrometric analyses have reported several post-translational modifications that possibly play an important role in modulating YBX1 function.Phosphorylation is the most widely occurring post-translational modification in YBX1.In vivo analyses of sites like S102 and more recently,S165 illustrate the relationship of post-translational regulation of YBX1 in promoting cell proliferation and tumor growth.This review provides a comprehensive and up-to-date account of post-translational modifications identified in YBX1.This knowledge is a key in allowing us to better understand the mechanism of YBX1 regulation,which will aid in development of novel therapeutic strategies to target YBX1 in many types of cancer in the future.展开更多
Protein arginine methyltransferase 5(PRMT5)deregulation has emerged as an important prognostic indicator in human cancers.Through aberrant methylation-mediated epige-netic modification of signaling molecules,PRMT5 ove...Protein arginine methyltransferase 5(PRMT5)deregulation has emerged as an important prognostic indicator in human cancers.Through aberrant methylation-mediated epige-netic modification of signaling molecules,PRMT5 over-expression contributes to dysregulation of a variety of cellular processes related to cancer progression.1 However,the mechanisms governing PRMT5 expression levels in cancer remain largely unknown.In this study,we examined factors that regulate PRMT5 expression at multiple levels.展开更多
基金This work was supported by grants from Indiana Center for Technology and Science Innovation(CTSl),USA(No.2286230 to TL)and Indiana Drug Discovery Alliance(IDDA),USA(No.2286233 to TL),both are funded in part by National Institutes of Health,USA(No.UL1TR002529)National Institutes of Health,USA(No.1R01GM120156-01A1 to TL+5 种基金No.R03 CA223906-01 to TL)This work was also supported by National Institutes of Health,USA(No.P41-GM103426 and DP20D007237 to REA),National Science Foundation,USA(No.CHE060073N to REA)National Institutes of Health,USA(No.R01 CA069202 to ZYZ)MLF and MRK were supported by IUSCCC Cancer Center,USA(No.P30 CA082709),National Institutes of Health,USA(No.R01CA167291and R01CA254110).MRK was also supported by National Institutes of Health,USA(No.R01CA205166,R01CA231267,and R01HL140961)MLF was also supported by National Institutes of Health,USA(No.R01CA211098,U01HL143403,and NF180045)MLF and MRK were additionally supported by the Riley Children's Foundation,USA.
文摘Market drugs,suchas Foodand Drug Administration(FDA)or European Medicines Agency(EMA)-approved drugs for specific indications provide opportunities for repurposing for newer therapeutics.This potentially saves resources invested in clinical trials that verify drug safety and tolerance in humans prior to alternative indication approval.Protein arginine methyltransferase 5(PRMT5)overexpression has been linked to promoting the tumor phenotype in several cancers,including pancreatic ductal adenocarcinoma(PDAC),colorectal cancer(CRC),and breast cancer(BC),making PRMT5 an important target for cancer therapy.Previously,we showed that PRMT5-mediated methylation of the nuclear factor(NF)-kB,partially contributes to its constitutive activation observed in cancers.In this study,we utilized an AlphaLiSA-based high-throughput screening method adapted in our lab,and identified one FDA-approved drug,Candesartan cilexetil(Can,used in hypertension treatment)and one EMA-approved drug,Cloperastine hydrochloride(Clo,used in cough treatment)that had significant PRMT5-inhibitory activity,and their anti-tumor properties were validated using cancer phenotypic assays in vitro.Furthermore,PRMT5 selective inhibition of methyltransferase activity was confirmed by reduction of both NF-kB methylation and its subsequent activation upon drug treatment.Using in silico prediction,we identified critical residues on PRMT5 targeted by these drugs that may interfere with its enzymatic activity.Finally,Clo and Can treatment have exhibited marked reduction in tumor growth in vivo.Overall,we provide basis for pursuing repurposing Clo and Can as anti-PRMT5 cancer therapies.Our study offers potential safe and fast repurposing of previously unknown PRMT5 inhibitors into clinical practice.
基金This research is supported by grants 4186265(American Cancer Society)and 23-862-07 and 036433730102(Indiana University)to TL.
文摘Y box binding protein-1(YBX1)belongs to a DNA-and RNA-binding family of transcription factors,containing the highly conserved cold shock domain(CSD).YBX1 is involved in a number of cellular functions including transcription,translation,DNA damage repair etc.,and it is upregulated during times of environmental stress.YBX1 is localized in both the cytoplasm and the nucleus.There,its nuclear translocation is observed in a number of cancers and is associated with poor prognosis and disease progression.Additionally,YBX1 expression is upregulated in a variety of cancers,pointing towards its role as a potential oncogene.Under certain circumstances,YBX1 also promotes the expression of multidrug resistance 1(MDR1)gene,which is involved in the development of drug resistance.Thus,it is critical to understand the mechanism of YBX1 regulation and its downstream effects on promoting cancer development.A number of recent studies have highlighted the mechanisms of YBX1 regulation.Mass spectrometric analyses have reported several post-translational modifications that possibly play an important role in modulating YBX1 function.Phosphorylation is the most widely occurring post-translational modification in YBX1.In vivo analyses of sites like S102 and more recently,S165 illustrate the relationship of post-translational regulation of YBX1 in promoting cell proliferation and tumor growth.This review provides a comprehensive and up-to-date account of post-translational modifications identified in YBX1.This knowledge is a key in allowing us to better understand the mechanism of YBX1 regulation,which will aid in development of novel therapeutic strategies to target YBX1 in many types of cancer in the future.
基金This publication is made possible,in part,with support from National Institutes of Health(NIH)Grants(No.1R01GM120156-01A1 and 1R03CA223906-01 to T.L.)。
文摘Protein arginine methyltransferase 5(PRMT5)deregulation has emerged as an important prognostic indicator in human cancers.Through aberrant methylation-mediated epige-netic modification of signaling molecules,PRMT5 over-expression contributes to dysregulation of a variety of cellular processes related to cancer progression.1 However,the mechanisms governing PRMT5 expression levels in cancer remain largely unknown.In this study,we examined factors that regulate PRMT5 expression at multiple levels.