Cancer-Associated, Interdependent Regulation of mTOR, AKT, and IKK/NF-kappaB

mTOR、AKT 和 IKK/NF-kappaB 的癌症相关、相互依赖的调节

• 批准号: 8019566
• 负责人: ALBERT Sidney BALDWIN
• 金额: $ 29.52万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-04-01 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8019566
• 关键词: Adenocarcinoma; Animal Cancer Model; Animal Model; Animals; Apoptosis; Apoptotic; Automobile Driving; Cancer Model; Cell Proliferation; Cell Survival; Cells; Complex; Cytostatics; Data; Development; Family; Feedback; Gene Expression; Genes; Genetic; Glioblastoma; Growth; Growth Factor; Growth Factor Receptors; Health; Human; Insulin; Knock-out; Malignant Neoplasms; Malignant neoplasm of prostate; Measures; Modeling; Molecular; Mutagenesis; Mutation; NF-kappa B; Nutrient; Oncogenic; Outcome; PC3 cell line; PTEN gene; Paper; Pathogenesis; Pathway interactions; Pharmaceutical Preparations; Phosphorylation; Phosphotransferases; Prostate; Prostatic Neoplasms; Proteins; Proto-Oncogene Proteins c-akt; Publishing; Raptors; Regulation; Relative (related person); Resistance; Role; Signal Transduction; Sirolimus; TSC2 gene; Testing; Therapeutic; Translations; Tumor Suppressor Proteins; Up-Regulation; Work; activating transcription factor; analog; base; cancer cell; cancer therapy; cell growth; clinically relevant; cytokine; cytotoxic; forkhead protein; human FRAP1 protein; in vitro Assay; inhibition of autophagy; inhibitor/antagonist; mTOR inhibition; neoplastic cell; novel; p65; receptor; receptor upregulation; reconstitution; research study; response; transcription factor; tumor; tumor growth; tumor progression; tumorigenesis

DESCRIPTION (provided by applicant): Akt is widely activated in a variety of cancers via (i) mutation in the PTEN tumor suppressor, (ii) activating mutations in PI3K, and (ii) through growth factor receptor upregulation/stimulation. Promotion of oncogenic mechanisms downstream of Akt involve stimulation of cellular proliferation and survival through phosphorylation of key substrates. For example, Akt is known to phosphorylate TSC2 to upregulate mTOR, to phosphorylate and inactivate pro-apoptotic Forkhead proteins, and to activate the transcription factor NF-kB (which functions in cell proliferation and survival). A key effector of the Akt pathway is mTOR, itself a kinase that functions in the TORC1 complex. Importantly, Akt is required for the development and progression of several animal models of cancer, and inhibition of mTOR with rapamycin blocks tumor growth induced by Akt. Additionally, a distinct mTOR complex (TORC2) containing the protein Rictor has been demonstrated to be the PDK2 activity that controls Akt activation via phosphorylation on ser473. Rapamycin, which blocks mTOR activity, has shown efficacy in certain cancers, but has failed in others due to a loss of a negative feedback pathway on IRS-1 and Akt activation. Thus, it is of extreme importance to understand potential regulatory mechanisms that could control both mTOR and Akt activation in cancers. We have published that IKK?, an upstream regulator of NF-kB pathway which is associated with oncogenesis, controls TORC1 activity in PTEN-null/inactive prostate cancers. A recently published paper from our group demonstrates that this interaction, reciprocally, leads to an mTOR/Raptor-dependent control of NF-kB activation controlling the expression of anti-apoptotic genes. Additionally, our preliminary data shows that IKK? associates with the TORC2 complex in PC3 prostate cancer cells to control Akt S473 phosphorylation and kinase activity. Thus, IKK? functions to regulate mTOR activity in both TORC1 and TORC2, raising the potential that IKK? inhibition could function to inhibit both TORC1 and TORC2, circumventing problems associated with rapamycin and its effects on feedback control of Akt activation. We propose to: (i) characterize mechanisms whereby IKK? controls TORC2 activity, determining if a specific IKK? inhibitor will block both TORC1 and TORC2 activity, (ii) determine if IKK??inhibition is cytotoxic/cytostatic in cancer cells and if this will block the loss of feedback control on IRS-1/Akt, and (iii) determine if genetic and pharmacologic inhibition of IKK? and/or IKK? will block progression and development of cancer in a PTEN-loss model of prostate cancer. As a human correlate, studies will be performed on primary human glioblastoma explants. The studies may identify a single mechanism to suppress mTOR and Akt activity in cancer. The studies are also the first to use a specific IKK? inhibitor for cancer studies.

描述（由申请人提供）：AKT通过（i）在PTEN肿瘤抑制器中的突变，（ii）PI3K中激活突变，以及（ii）通过生长因子受体上调/刺激激活突变。促进Akt下游的致癌机制涉及通过关键底物的磷酸化刺激细胞增殖和存活。例如，已知AKT磷酸化TSC2以上调MTOR，以磷酸化和失活促凋亡叉子蛋白，并激活转录因子NF-KB（在细胞增殖和存活中起作用）。 AKT途径的关键效应子是MTOR，它本身是一种在TORC1复合物中起作用的激酶。重要的是，几种癌症动物模型的发展和进展需要AKT，以及用雷帕霉素阻断MTOR抑制AKT诱导的肿瘤生长。此外，已证明包含蛋白质rictor的独特MTOR复合物（TORC2）是通过Ser473上磷酸化控制Akt激活的PDK2活性。雷帕霉素阻断了MTOR活性，它在某些癌症中表现出了功效，但由于IRS-1和AKT激活的负反馈途径的丢失，在其他癌症中已经失败了。因此，了解可以控制癌症中MTOR和AKT激活的潜在调节机制至关重要。 我们已经发表了IKK？，是NF-KB途径的上游调节剂，它与肿瘤发生有关，控制PTEN-NULL/非活性前列腺癌中的Torc1活性。我们小组最近发表的一篇论文表明，这种相互作用以相互的相互作用导致控制抗凋亡基因表达的NF-KB激活的MTOR/RAPTOR依赖性控制。此外，我们的初步数据表明IKK？与PC3前列腺癌细胞中的TORC2复合物相关联，以控制AKT S473磷酸化和激酶活性。因此，IKK？在TORC1和TORC2中调节MTOR活性的功能，从而提高了IKK的潜力？抑制作用可以抑制TORC1和TORC2，从而规避与雷帕霉素有关的问题及其对Akt激活反馈控制的影响。我们建议：（i）表征IKK的机制？控制TORC2活动，确定特定的IKK？抑制剂会阻止TORC1和TORC2活性，（ii）确定IKK抑制是否是癌细胞中的细胞毒性/细胞抑制作用，并且是否会阻止IRS-1/AKT的反馈控制丧失，并且（iii）确定遗传和药理学抑制IKK？和/或IKK？将在前列腺癌模型中阻止癌症的进展和发展。作为人类的相关性，将对原代人胶质母细胞瘤外植体进行研究。这些研究可能会确定一种抑制癌症MTOR和AKT活性的单一机制。研究也是第一个使用特定IKK的研究？癌症研究抑制剂。