Regulation and Role of Ornithine Decarboxylase in Cell Proliferation and Cancer

鸟氨酸脱羧酶在细胞增殖和癌症中的调节和作用

• 批准号: 8383056
• 负责人: John L. Cleveland
• 金额: $ 39.23万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-03-04 至 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8383056
• 关键词: Address; Affect; Anabolism; Apoptosis; B lymphoid malignancy; B-Cell Lymphomas; B-Lymphocytes; Binding; Boxing; Breast Adenocarcinoma; Carcinogens; Cell Cycle Arrest; Cell Proliferation; Cell division; Cells; Chemoprevention; Clinic; Clinical Trials; Colon Carcinoma; Complex; Cyclin-Dependent Kinase Inhibitor; DL-alpha-Difluoromethylornithine; Data; Development; Dimerization; Dose; Down-Regulation; Early Diagnosis; Enzymes; Family; Funding; Genes; Genetic; Genetic Transcription; Genome; Goals; Homeostasis; Human; Knockout Mice; Lead; Letters; Longevity; Lung Adenocarcinoma; Lymphoma; Lymphomagenesis; Maintenance; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of prostate; Mediating; Mediator of activation protein; Metabolic; Metabolism; Mission; Modeling; Mus; Mutate; Mutation; Nature; Neuroblastoma; Normal Cell; Oncogene Proteins; Oncogenes; Oncogenic; Ornithine Decarboxylase; Papilloma; Pathway interactions; Play; Polyamines; Premalignant; Protein p53; Proteins; Putrescine; Refractory; Regulation; Research Support; Resistance; Role; S Phase; Signal Transduction; Skin Neoplasms; Tamoxifen; Testing; Therapeutic Index; Therapy Clinical Trials; Transgenic Mice; Tumor Suppressor Proteins; addiction; base; cancer cell; cancer chemoprevention; cancer prevention; cancer therapy; carcinogenesis; cell growth; clinically relevant; cyclin-dependent kinase inhibitor 1B; expectation; inhibitor/antagonist; loss of function mutation; malignant breast neoplasm; malignant state; mouse model; multicatalytic endopeptidase complex; mutant; neoplastic cell; outcome forecast; prevent; programs; protein expression; ras Oncogene; response; suicide inhibitor; transcription factor; tumor; tumorigenesis; ubiquitin-protein ligase

Project Summary The Myc family of oncogenic transcription factors is activated in ~70% of human cancers and they regulate the transcription of a large cast (10-15%) of the genome to coordinate metabolism, cell growth and division, differentiation, and development. Further, Myc lies downstream of activated Ras oncoproteins that are frequently mutated in human cancers, where Ras signaling impairs turnover of Myc protein and augments its transcriptional activity. Over the past funding cycle we demonstrated that Myc's proliferative response is rate limiting for tumor development. Remarkably, this pathway strictly relies on a single Myc transcription target, ornithine decarboxylase (Odc), the rate limiting enzyme of polyamine biosynthesis. Here we demonstrated that treatment with the Odc suicide inhibitor DFMO, or simply halving the levels of Odc (in Odc+/- mice), triples the lifespan of tumor-prone, Myc transgenic mice and that it also impairs epidermal carcinogenesis, which is associated with activating mutations in Ras. Collectively, these findings suggest that targeting Odc will have widespread benefit in cancer prevention, a fact now validated in ongoing human cancer chemoprevention trials. Further, we established that targeting Odc disables Myc's proliferative response by selectively affecting Myc's ability to provoke the degradation of the cyclin- dependent kinase inhibitor p27Kip1, a tumor suppressor that inhibits entry and progression through S-phase. Here we first demonstrated that Myc triggers p27Kip1 degradation by activating the transcription of Cks1, a component of the SCFSkp2 E3 ubiquitin ligase complex that directs p27Kip1 destruction. Surprisingly, we have now shown that Odc is required for Myc to induce Cks1 transcription. Collectively, these findings suggest a Myc>Odc>Cks1-to-p27Kip1 pathway drives Myc-induced proliferation and tumorigenesis. Using validated Myc-driven mouse models of B cell lymphoma and mammary adenocarcinoma, and of K-Ras-directed lung adenocarcinoma, we will test the roles of Odc in oncogene-driven proliferation and tumor development, the maintenance of the malignant state, and its interplay with tumor suppressor pathways. These studies include those that evaluate potential therapeutic index, where the intrinsic effects of Odc loss on pre- existing tumor cells versus its effects in normal cells will be determined. We will also critically assess the roles of p27Kip1 and Cks1 as downstream targets of Odc in cancer development and tumor maintenance, and will define the mechanism by which Odc regulates Cks1 and p27Kip1 expression. Given the pervasive and aggressive nature of Myc- and Ras-associated malignancies in human cancer, especially in the three malignancies interrogated herein, and clinical trials establishing the efficacy of targeting Odc in human cancer chemoprevention, the proposed studies are clearly highly relevant to the mission of the NCI.

项目摘要 Myc家族的致癌转录因子在约70%的人类癌症中被激活，并且它们调节 基因组的大铸件（10-15%）的转录，以协调代谢，细胞生长和分裂， 分化和发展。 此外，Myc位于激活的Ras癌蛋白的下游， 在人类癌症中经常发生突变，其中Ras信号传导损害Myc蛋白的周转，并增加 其转录活性。在过去的资助周期中，我们证明了Myc的增殖反应 是肿瘤发展的限速因子 值得注意的是，这一途径严格依赖于一个单一的Myc 多胺生物合成的限速酶--鸟氨酸脱羧酶（Odc）。 在这里，我们证明了用Odc自杀抑制剂DFMO治疗，或者简单地将Odc水平减半， Odc（在Odc+/-小鼠中）使易患肿瘤的Myc转基因小鼠的寿命延长三倍， 表皮癌发生，这与Ras的激活突变有关。总的来说，这些发现 表明靶向Odc将在癌症预防中具有广泛益处，这一事实现已在 正在进行的人类癌症化学预防试验。此外，我们确定，针对Odc禁用Myc的 通过选择性地影响Myc引起细胞周期蛋白降解的能力， 依赖性激酶抑制剂p27 Kip 1，一种抑制S期进入和进展的肿瘤抑制剂。 在此，我们首次证明Myc通过激活Cks 1的转录而触发p27 Kip 1降解， 指导p27 Kip 1破坏的SCFSkp 2 E3泛素连接酶复合物的组分。令人惊讶的是， 现在表明Odc是Myc诱导Cks 1转录所必需的。总的来说，这些发现表明， Myc>Odc> Cks 1-to-p27 Kip 1通路驱动Myc诱导的增殖和肿瘤发生。使用经验证的 Myc驱动的B细胞淋巴瘤和乳腺癌小鼠模型以及K-Ras导向的肺 腺癌，我们将测试Odc在癌基因驱动的增殖和肿瘤发展中的作用， 恶性状态的维持及其与肿瘤抑制途径的相互作用。 这些研究 包括那些评估潜在治疗指数，其中Odc损失对前 将确定现有的肿瘤细胞与其对正常细胞的影响。我们还将严格评估 p27 Kip 1和Cks 1作为Odc下游靶点在癌症发展和肿瘤维持中的作用， 将定义Odc调节Cks 1和p27 Kip 1表达的机制。鉴于普遍存在的和 Myc和Ras相关恶性肿瘤在人类癌症中的侵袭性，特别是在三种 本文中询问的恶性肿瘤，以及建立靶向Odc在人类中的功效的临床试验。 癌症化学预防，所提出的研究显然与NCI的使命高度相关。

项目成果

Targeting ornithine decarboxylase impairs development of MYCN-amplified neuroblastoma.

• DOI: 10.1158/0008-5472.can-08-2968
• 发表时间: 2009-01-15
• 期刊: Cancer research
• 影响因子: 11.2
• 作者: Rounbehler RJ;Li W;Hall MA;Yang C;Fallahi M;Cleveland JL
• 通讯作者: Cleveland JL

Activation of endoplasmic reticulum stress response by enhanced polyamine catabolism is important in the mediation of cisplatin-induced acute kidney injury.

• DOI: 10.1371/journal.pone.0184570
• 发表时间: 2017
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Zahedi K;Barone S;Destefano-Shields C;Brooks M;Murray-Stewart T;Dunworth M;Li W;Doherty JR;Hall MA;Smith RD;Cleveland JL;Casero RA Jr;Soleimani M
• 通讯作者: Soleimani M