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 前列腺癌（PCa）是男性中最常见的诊断癌症， 美国癌症相关死亡的原因复发性雄激素信号传导与肿瘤内固醇 生物合成是去势抵抗性PCa（CRPC）的标志。PCa生长和增殖 依赖于雄激素受体（AR）的雄激素信号传导。针对雄激素 AR的合成途径和反式激活功能是治疗AR的主要治疗方法 PCa。PCa从去势敏感期到去势抵抗期（CRPC）的进展 依赖于雄激素信号拮抗剂的失败和AR中心的调节失调， 高比例患者的分子机制。最近的研究表明，microRNAs （miRNAs）通过靶向癌基因和靶向转录后调节基因表达， 在包括PCa在内的各种癌症中执行肿瘤抑制功能。科学前提： 激发这项研究的基本发现是miR-149- 5 p靶向 两种主要转录因子AR和固醇调节元件结合的表达 转录因子1（SREBF 1），两者都是可药物化的目标，并涉及CRPC。我们 中心假设需要miR-149- 5 p转录后下调AR， SREBF 1和miR-149- 5 p表达的失活导致前列腺癌发生 雄激素信号传导和甾醇生物合成的上调，其促进CRPC。我们将 通过追求三个综合的具体目标来验证我们的假设。在目标1中，我们将测试miR-149- 5 p 在目的2中，我们将定义PCa细胞中的抗增殖和抗致癌功能的分子生物学特性。 对miR-149- 5 p成熟产生负面影响的机制，在目的3中，我们将测试 miR-149- 5 p的治疗和预后价值。意义：本研究将提供 miR-149- 5 p在CRPC中的肿瘤抑制作用。创新的研究方法 一种新的miRNA介导的雄激素信号传导和肿瘤内固醇控制引起的疾病 通过直接共靶向AR和 SREBF 1，两者都是CRPC中的药物靶点。这项研究有可能测试 首次共靶向初级PCa促进转录因子， 通过鉴定雄激素信号传导的重要关键调节因子来改善患者治疗 和甾醇生物合成途径。

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

The androgen receptor messenger RNA: what do we know?

• DOI: 10.1080/15476286.2022.2084839
• 发表时间: 2022-01
• 期刊: RNA BIOLOGY
• 影响因子: 4.1
• 作者: Likos, Eviania;Bhattarai, Asmita;Weyman, Crystal M.;Shukla, Girish C.
• 通讯作者: Shukla, Girish C.

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