Elucidation of MLK3 Signaling in Hepatocellular Carcinoma

肝细胞癌中 MLK3 信号传导的阐明

• 批准号: 10324547
• 负责人: BASABI RANA
• 金额: --
• 依托单位: JESSE BROWN VA MEDICAL CENTER
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/10324547
• 关键词: APC gene; APC mutation; Adult; Agonist; Alcoholism; Animals; BAY 54-9085; BCL2L1 gene; Cause of Death; Cell Cycle Arrest; Cell physiology; Ceramides; Childhood Liver Cancer; Combined Modality Therapy; Complex; Cyclin D1; Development; Diabetes Mellitus; Disease; Etiology; Event; FRAP1 gene; Family; Fatty Liver; Financial Hardship; Future; Genes; Genetic Diseases; Genetic Transcription; Goals; Hepatitis; Hepatitis B Virus; Hepatitis C virus; Human; In Vitro; Inflammation; Injury; Link; Liver Cirrhosis; Liver neoplasms; M cell; Malignant Epithelial Cell; Malignant Neoplasms; Malignant neoplasm of gastrointestinal tract; Mediating; Mediator of activation protein; Medical; Mitogen-Activated Protein Kinase Kinases; Modeling; Molecular; Mus; Mutation; Nuclear Translocation; Obesity; Oncogenic; PI3K/AKT; Pathway interactions; Patients; Pharmaceutical Preparations; Phosphotransferases; Primary carcinoma of the liver cells; Proteins; Proto-Oncogene Proteins c-akt; Regulation; Reporting; Role; Signal Pathway; Signal Transduction; Signaling Protein; TCF Transcription Factor; Testing; Therapeutic; Tumor Suppressor Proteins; Veterans; Viral hepatitis; WNT Signaling Pathway; antagonist; base; beta catenin; c-myc Genes; cancer cell; chronic liver disease; design; effective therapy; glycogen synthase kinase 3 beta; in vivo; in vivo Model; inhibitor; insight; liver cancer model; military veteran; mixed lineage kinase 3; mutant; nanoparticle; new therapeutic target; next generation; non-alcoholic; nonalcoholic steatohepatitis; novel; overexpression; problem drinker; public health relevance; survivin; targeted treatment; therapy resistant; transcription factor

 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

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: Oncotarget
• 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: Proceedings of the National Academy of Sciences of the United States of America
• 影响因子: 11.1

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: Scientific reports
• 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: Cancer letters
• 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: CELL DEATH & DISEASE
• 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