Androgen signaling and sterol metabolism in metastatic prostate cancer: Functional and therapeutic implication

转移性前列腺癌中的雄激素信号传导和甾醇代谢：功能和治疗意义

• 批准号: 10201013
• 负责人: Girish C Shukla
• 金额: $ 41.24万
• 依托单位: CLEVELAND STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10201013
• 关键词: Academic Research Enhancement Awards; Affect; American; Anabolism; Androgen Antagonists; Androgen Receptor; Androgens; Animal Model; Animals; Binding; Binding Proteins; Biochemistry; Biology; CWR22Rv1; Cancer Etiology; Cancer Patient; Castration; Cell model; Cessation of life; Cholesterol; Coenzyme A; Cytoplasm; Development; Disease; Down-Regulation; Educational process of instructing; Enzymes; Failure; Gene Expression Regulation; Genes; Genetic Polymorphism; Genetic Transcription; Grant; Growth; Hydroxymethylglutaryl-CoA reductase; Laboratories; Ligands; Link; Longevity; Luteinizing Hormone-releasing Hormone Agonist; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Membrane; Metabolism; Metastatic Prostate Cancer; Methods; MicroRNAs; Molecular; Nature; Neoplasm Metastasis; Oncogenes; Oncogenic; Outcome; Pathway interactions; Patients; Play; Post-Transcriptional Regulation; Prognosis; Prognostic Marker; Prostate Cancer therapy; Proteins; RNA; Regulation; Regulatory Element; Relapse; Research; Resistance; Resources; Role; Sampling; Serum; Signal Transduction; Single Nucleotide Polymorphism; Sterol Biosynthesis Pathway; Sterols; Testing; Testosterone; Therapeutic; Time; Transactivation; Tumor Suppressor Proteins; Up-Regulation; Xenograft procedure; abiraterone; androgen deprivation therapy; biomarker discovery; cancer diagnosis; cancer therapy; castration resistant prostate cancer; curative treatments; design; doctoral student; druggable target; graduate student; improved; innovation; men; mouse model; negative affect; novel; novel therapeutics; prognostic; prognostic significance; prognostic value; prostate cancer cell; prostate cancer cell line; prostate cancer model; prostate cancer progression; prostate carcinogenesis; public health relevance; testosterone biosynthesis; therapeutic evaluation; transcription factor; tumor; undergraduate student

Abstract Prostate cancer (PCa) is the most commonly diagnosed cancer in men and the second leading cause of cancer-related deaths in the USA. Relapsed androgen signaling and intratumoral sterol biosynthesis are hallmarks of castration-resistant PCa (CRPC). PCa growth and proliferation depend on androgen signaling by the Androgen Receptor (AR). Targeting the androgen synthesis pathways and transactivation function of AR is a primary therapeutic approach to treat PCa. The progression of PCa from castration-sensitive to the castration-resistant stage (CRPC) depends on the failure of androgen signaling antagonists and the dysregulation of AR-centric molecular mechanisms in a high percentage of patients. Recent studies show that microRNAs (miRNAs) exert post-transcriptional regulation of gene expression by targeting oncogenes and performing tumor-suppressive functions in various cancers, including PCa. Scientific premise: The fundamental discovery motivating the proposed study is that miR-149-5p targets the expression of two major transcription factors AR and sterol regulatory element-binding transcription factor 1 (SREBF1), both are druggable targets and are implicated in CRPC. Our central hypothesis entails that miR-149-5p post-transcriptionally downregulates AR and SREBF1, and inactivation of miR-149-5p expression during the prostate carcinogenesis leads to the upregulation of androgen signaling and sterol biosynthesis, which promotes CRPC. We will test our hypothesis by pursuing three integrated Specific Aims. In aim 1 we will test miR-149-5p anti-proliferation and anti-oncogenic function in PCa cells, in Aim 2, we will define molecular mechanisms which negatively affects the maturation of miR-149-5p and in the aim 3, we will test the therapeutic and prognostic value of miR-149-5p. Significance: The study will provide a tumor-suppressor role of miR-149-5p in CRPC. The innovative research approaches the disease from a novel miRNA-mediated control of the androgen signaling and intratumoral sterol biosynthesis pathways in particular testosterone metabolism by directly co-targeting AR and SREBF1, and both are druggable targets in CRPC. This study has the potential to test for the first time co-targeting of primary PCa promoting transcription factors and a new paradigm for improved patient therapies by identifying the significant key regulators of androgen signaling and sterol biosynthesis pathways.

摘要

项目成果

Survival analysis and prognostic factors of the carcinoma of gallbladder.

• DOI: 10.1186/s12957-022-02857-y
• 发表时间: 2022-12-20
• 期刊: WORLD JOURNAL OF SURGICAL ONCOLOGY
• 影响因子: 3.2
• 作者: Feroz, Zainab;Gautam, Priyanka;Tiwari, Sonia;Shukla, Girish C.;Kumar, Munish
• 通讯作者: Kumar, Munish

Investigating the Role of Glutathione S- Transferase Genes, Histopathological and Molecular Subtypes, Gene-Gene Interaction and Its Susceptibility to Breast Carcinoma in Ethnic North- Indian Population.

研究谷胱甘肽S-转移酶基因，组织病理学和分子亚型，基因基因相互作用及其对北印度种群中乳腺癌的敏感性的作用。

• DOI: 10.31557/apjcp.2022.23.10.3481
• 发表时间: 2022-10-01
• 期刊: Asian Pacific journal of cancer prevention : APJCP
• 作者: Gautam, Priyanka;Feroz, Zainab;Tiwari, Sonia;Vijayraghavalu, Sivakumar;Shukla, Girish C;Kumar, Munish
• 通讯作者: Kumar, Munish

Differential Expression of Non-Coding RNAs in Stem Cell Development and Therapeutics of Bone Disorders.

• DOI: 10.3390/cells12081159
• 发表时间: 2023-04-14
• 期刊: Cells
• 影响因子: 6

Metabolic Pathways, Enzymes, and Metabolites: Opportunities in Cancer Therapy.

• DOI: 10.3390/cancers14215268
• 发表时间: 2022-10-27
• 期刊: Cancers
• 影响因子: 5.2

Higher order genes interaction in DNA repair and cytokine genes polymorphism and risk to lung cancer in North Indians.

北印度人 DNA 修复和细胞因子基因多态性以及肺癌风险中的高阶基因相互作用。

• DOI: 10.4103/jcrt.jcrt_51_20
• 发表时间: 2022
• 期刊: Journal of cancer research and therapeutics
• 影响因子: 1.3
• 作者: Ritambhara;Kumar,Rishabh;Gupta,ManeeshKumar;Gautam,Priyanka;Tiwari,Sonia;Vijayraghavalu,Sivakumar;Shukla,GirishC;Kumar,Munish
• 通讯作者: Kumar,Munish