Elucidation of MLK3 Signaling in Hepatocellular Carcinoma
肝细胞癌中 MLK3 信号传导的阐明
基本信息
- 批准号:10324547
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-01-01 至 2021-12-31
- 项目状态:已结题
- 来源:
- 关键词:APC geneAPC mutationAdultAgonistAlcoholismAnimalsBAY 54-9085BCL2L1 geneCause of DeathCell Cycle ArrestCell physiologyCeramidesChildhood Liver CancerCombined Modality TherapyComplexCyclin D1DevelopmentDiabetes MellitusDiseaseEtiologyEventFRAP1 geneFamilyFatty LiverFinancial HardshipFutureGenesGenetic DiseasesGenetic TranscriptionGoalsHepatitisHepatitis B VirusHepatitis C virusHumanIn VitroInflammationInjuryLinkLiver CirrhosisLiver neoplasmsM cellMalignant Epithelial CellMalignant NeoplasmsMalignant neoplasm of gastrointestinal tractMediatingMediator of activation proteinMedicalMitogen-Activated Protein Kinase KinasesModelingMolecularMusMutationNuclear TranslocationObesityOncogenicPI3K/AKTPathway interactionsPatientsPharmaceutical PreparationsPhosphotransferasesPrimary carcinoma of the liver cellsProteinsProto-Oncogene Proteins c-aktRegulationReportingRoleSignal PathwaySignal TransductionSignaling ProteinTCF Transcription FactorTestingTherapeuticTumor Suppressor ProteinsVeteransViral hepatitisWNT Signaling Pathwayantagonistbasebeta cateninc-myc Genescancer cellchronic liver diseasedesigneffective therapyglycogen synthase kinase 3 betain vivoin vivo Modelinhibitorinsightliver cancer modelmilitary veteranmixed lineage kinase 3mutantnanoparticlenew therapeutic targetnext generationnon-alcoholicnonalcoholic steatohepatitisnoveloverexpressionproblem drinkerpublic health relevancesurvivintargeted treatmenttherapy resistanttranscription factor
项目摘要
DESCRIPTION (provided by applicant):
Hepatocellular carcinoma (HCC) is one of the most common gastrointestinal (GI) malignancies and a major cause of death worldwide, with limited therapeutic options. Chronic liver diseases are believed to contribute significantly towards the development and progression of HCC due to their role in inflammation and injury. These chronic liver diseases including hepatitis, fatty live diseases (alcoholic and nonalcoholic) are prevalent among our veterans, thus creating a significant financial and medical burden. The only drug currently available to treat HCC is the multikinase inhibitor Sorafenib, which is effective only for a few months. Designing safe and efficient therapeutic approaches that can target additional signaling axes (aberrant in HCC) is critical for treating this deadly form of malignancy. Activation of various oncogenic pathways have been reported in HCC, which include PI3K/AKT/mTOR and Wnt/β-catenin signaling cascades, for which little or no effective therapies are available currently. Of particular importance is the Wnt/β-catenin pathway, since oncogenic mutations of β- catenin have been reported in a number of adult and childhood liver cancers. Attempts to develop drugs that can effectively target the Wnt/β-catenin axis has been extremely challenging mostly due to the fact that β- catenin is an intracellular protein without any enzymatic activity, and thus this axis is currently considered "undruggable". This is further complicated by the fact that β-catenin can localize in various cellular compartments and mediate multiple cellular functions some of which are paradoxical. Identification of specific upstream signaling pathways that can modulate β-catenin axis is thus critically needed to develop targeted therapies for HCC patients with aberrant activation of this axis. Our recent studies revealed a novel signaling pathway mediated by Mixed Lineage Kinase 3 (MLK3), a MAPK Kinase Kinase (MAP3K) that impacts β- catenin-mediated oncogenic signaling. Our studies indicate that MLK3 can phosphorylate and stabilize β- catenin in cancer cells, which involves a novel pathway independent of GSK3β. Despite stabilizing β-catenin, MLK3 inhibited β-catenin/TCF-dependent transcriptional activity and ultimately resulted in G2/M cell cycle arrest. Based on the preliminary results, we hypothesize that MLK3 activation can successfully antagonize HCC progression via inhibiting conventional Wnt/β-catenin pathway. The current proposal aims to validate our hypothesis utilizing both in vitro (cellular) and in vivo (animal) models while elucidating the fundamental mechanisms by which MLK3 modulates β-catenin pathway in HCC. The following specific aims are proposed to achieve our goals: (i) Determine the role of MLK3 in modulating Wnt/β-catenin axis in HCC cells, (ii) Elucidate the molecular mechanism of MLK3-induced modulation of Wnt/β-catenin axis in HCC cells and (iii) Determine the role of MLK3 in antagonizing Wnt/β-catenin axis in an in vivo model of HCC. Upon completion of these aims, we expect to establish the in vivo role of MLK3 in antagonizing Wnt/β-catenin axis in HCC, and identify the potential mechanism, which can be utilized for developing targeted therapeutic options in the future. The studies with the phospho-β-catenin mutants are expected to provide novel mechanistic insight revealing how this antagonism is achieved and identify new regulators of Wnt/β-catenin axis. Combined together, this information can be utilized to develop the next generation (more potent) MLK3 agonists to be utilized as monotherapy or in combination therapies to specifically target the β-catenin axis i HCC patients.
项目成果
期刊论文数量(18)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Modulation of glycogen synthase kinase-3β following TRAIL combinatorial treatment in cancer cells.
- DOI:10.18632/oncotarget.11834
- 发表时间:2016-10-11
- 期刊:
- 影响因子:0
- 作者:Santha S;Davaakhuu G;Basu A;Ke R;Das S;Rana A;Rana B
- 通讯作者:Rana B
Calcium channel blockers potentiate gemcitabine chemotherapy in pancreatic cancer.
- DOI:10.1073/pnas.2200143119
- 发表时间:2022-05-03
- 期刊:
- 影响因子:11.1
- 作者:
- 通讯作者:
Involvement of AMP-activated protein kinase and Death Receptor 5 in TRAIL-Berberine-induced apoptosis of cancer cells.
- DOI:10.1038/s41598-018-23780-x
- 发表时间:2018-04-03
- 期刊:
- 影响因子:4.6
- 作者:Ke R;Vishnoi K;Viswakarma N;Santha S;Das S;Rana A;Rana B
- 通讯作者:Rana B
Mixed Lineage Kinase 3 phosphorylates prolyl-isomerase PIN1 and potentiates GLI1 signaling in pancreatic cancer development.
- DOI:10.1016/j.canlet.2021.04.015
- 发表时间:2021-09-01
- 期刊:
- 影响因子:9.7
- 作者:Viswakarma N;Sondarva G;Principe DR;Nair RS;Kumar S;Singh SK;Das S;Sinha SC;Grippo PJ;Grimaldo S;Giulianotti PC;Rana B;Rana A
- 通讯作者:Rana A
Ets1 mediates sorafenib resistance by regulating mitochondrial ROS pathway in hepatocellular carcinoma.
- DOI:10.1038/s41419-022-05022-1
- 发表时间:2022-07-04
- 期刊:
- 影响因子:9
- 作者:Vishnoi, Kanchan;Ke, Rong;Viswakarma, Navin;Srivastava, Piush;Kumar, Sandeep;Das, Subhasis;Singh, Sunil Kumar;Principe, Daniel R.;Rana, Ajay;Rana, Basabi
- 通讯作者:Rana, Basabi
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
BASABI RANA其他文献
BASABI RANA的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('BASABI RANA', 18)}}的其他基金
Mixed Lineage Kinase 3 and cytokine signaling axis in hepatocellular carcinoma
肝细胞癌中的混合谱系激酶 3 和细胞因子信号轴
- 批准号:
10527344 - 财政年份:2021
- 资助金额:
-- - 项目类别:
Mixed Lineage Kinase 3 and cytokine signaling axis in hepatocellular carcinoma
肝细胞癌中的混合谱系激酶 3 和细胞因子信号轴
- 批准号:
10365639 - 财政年份:2021
- 资助金额:
-- - 项目类别:
Elucidation of MLK3 Signaling in Hepatocellular Carcinoma
肝细胞癌中 MLK3 信号传导的阐明
- 批准号:
9032316 - 财政年份:2016
- 资助金额:
-- - 项目类别:
Elucidation of MLK3 Signaling in Hepatocellular Carcinoma
肝细胞癌中 MLK3 信号传导的阐明
- 批准号:
10038787 - 财政年份:2016
- 资助金额:
-- - 项目类别:
Elucidation of MLK3 Signaling in Hepatocellular Carcinoma
肝细胞癌中 MLK3 信号传导的阐明
- 批准号:
9256218 - 财政年份:2016
- 资助金额:
-- - 项目类别:
Role of beta-catenin in apoptosis resistance of hepatocellular carcinoma
β-catenin在肝细胞癌凋亡抵抗中的作用
- 批准号:
8854052 - 财政年份:2014
- 资助金额:
-- - 项目类别:
Role of beta-catenin in apoptosis resistance of hepatocellular carcinoma
β-catenin在肝细胞癌凋亡抵抗中的作用
- 批准号:
9487175 - 财政年份:2014
- 资助金额:
-- - 项目类别:
Role of beta-catenin in apoptosis resistance of hepatocellular carcinoma
β-catenin在肝细胞癌凋亡抵抗中的作用
- 批准号:
8694742 - 财政年份:2014
- 资助金额:
-- - 项目类别:
Role of beta-catenin in apoptosis resistance of hepatocellular carcinoma
β-catenin在肝细胞癌凋亡抵抗中的作用
- 批准号:
9190200 - 财政年份:2014
- 资助金额:
-- - 项目类别:
Molecular Mechanisms of Gastrin Mediated Pathways in Gastric Cancer Cells
胃癌细胞胃泌素介导途径的分子机制
- 批准号:
8045809 - 财政年份:2011
- 资助金额:
-- - 项目类别:
相似海外基金
APC mutation and breast cancer: Prevention by curcumin
APC 突变与乳腺癌:姜黄素预防
- 批准号:
7620114 - 财政年份:2006
- 资助金额:
-- - 项目类别:
APC mutation and breast cancer: Prevention by curcumin
APC 突变与乳腺癌:姜黄素预防
- 批准号:
7425971 - 财政年份:2006
- 资助金额:
-- - 项目类别:
APC mutation and breast cancer: Prevention by curcumin
APC 突变与乳腺癌:姜黄素预防
- 批准号:
7247167 - 财政年份:2006
- 资助金额:
-- - 项目类别:
APC mutation and breast cancer: Prevention by curcumin
APC 突变与乳腺癌:姜黄素预防
- 批准号:
7132974 - 财政年份:2006
- 资助金额:
-- - 项目类别:
APC mutation and breast cancer: Prevention by curcumin
APC 突变与乳腺癌:姜黄素预防
- 批准号:
8260721 - 财政年份:2006
- 资助金额:
-- - 项目类别:
APC mutation and breast cancer: Prevention by curcumin
APC 突变与乳腺癌:姜黄素预防
- 批准号:
7813928 - 财政年份:2006
- 资助金额:
-- - 项目类别:
APC mutation and the initiation of colorectal cancer
APC突变与结直肠癌的发生
- 批准号:
nhmrc : 400251 - 财政年份:2006
- 资助金额:
-- - 项目类别:
NHMRC Project Grants
Development of novel screening method by detection of APC mutation from colorectal cancer cells in stool
开发粪便中结直肠癌细胞APC突变检测新筛查方法
- 批准号:
17591404 - 财政年份:2005
- 资助金额:
-- - 项目类别:
Grant-in-Aid for Scientific Research (C)
DIETARY INTERACTIONS WITH APC MUTATION IN COLON CANCER
饮食与结肠癌 APC 突变的相互作用
- 批准号:
2748805 - 财政年份:1995
- 资助金额:
-- - 项目类别:
DIETARY INTERACTIONS WITH APC MUTATION IN COLON CANCER
饮食与结肠癌 APC 突变的相互作用
- 批准号:
2111759 - 财政年份:1995
- 资助金额:
-- - 项目类别: