PDLIM2 as a cancer and chemosensitizing target
PDLIM2 作为癌症和化疗增敏靶点
基本信息
- 批准号:8685914
- 负责人:
- 金额:$ 30.95万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2013
- 资助国家:美国
- 起止时间:2013-07-01 至 2018-04-30
- 项目状态:已结题
- 来源:
- 关键词:Adjuvant TherapyAdult T-Cell Leukemia/LymphomaApplications GrantsBreastCancer EtiologyCarboplatinCessation of lifeChemosensitizationClinical TrialsColonColon CarcinomaDNADNA MethyltransferaseDNA Modification MethylasesDevelopmentDiagnosisEpigenetic ProcessGene TargetingGenetic TranscriptionGoalsGrowthHumanImmune responseIn VitroKnock-outLIM DomainLeadLinkLungLung NeoplasmsMalignant NeoplasmsMalignant neoplasm of lungMediatingMolecularMulti-Drug ResistanceMusNuclearPathogenesisPatientsPharmaceutical PreparationsPhysiologicalPhysiologyPlatinumPlayPreventionProteinsRNARecruitment ActivityRepressionResearchResistanceRoleSmokingTestingTherapeuticTranslatingTumor Suppressor ProteinsTumorigenicityUnited Statesanticancer researchbasecancer cellcancer therapycancer typechemosensitizing agentchemotherapyeffective therapyimprovedin vivoinhibitor/antagonistinnovationlung cancer preventionlung tumorigenesismutantnew therapeutic targetnovelnovel diagnosticsnovel strategiesoutcome forecastp65preclinical studypreventpromoterpublic health relevancereconstitutionresponsetranscription factortumortumorigenesisubiquitin-protein ligase
项目摘要
DESCRIPTION (provided by applicant): Chemotherapy remains the standard first-line treatment for many cancers, including lung cancer, the leading cause of cancer deaths responsible for approximately 160,000 deaths every year in the United States alone. However, the benefits of current chemotherapy are very limited due to intrinsic and acquired resistance of cancer cells. The long-term goal of our research is to understand the mechanisms underlying tumorigenesis and chemoresistance, and to translate this understanding into novel approaches to improve cancer cure rates by establishing new effective therapies and/or priming cancer cells to respond to current therapeutic drugs. To this end, we have recently identified PDLIM2, a ubiquitously expressed PDZ-LIM domain-containing protein with the highest level in lungs, as a suppressor of lung cancer and several other cancer types such as adult T-cell leukemia/lymphoma (ATL), breast, and colon cancers. We find that the expression of PDLIM2 is epigenetically repressed in these cancer cells, and that PDLIM2 reconstitution prevents their tumorigenicity. Moreover, PDLIM2 deficiency predisposes mice to spontaneous and induced cancers, particularly lung cancer. Notably, the repression of PDLIM2 expression is associated with the chemotherapy resistance of lung cancer, and PDLIM2 re-induction is required for the epigenetic drug 5-aza-dC to induce growth inhibition and response to the chemotherapeutic drug carboplatin in multidrug resistant lung cancer cells. Mechanistic studies indicate that PDLIM2 functions as a ubiquitin E3 ligase to selectively degrade nuclear (activated) NF- ?B RelA (also known as p65), a transcription factor that has been suggested to play a causative role in tumorigenesis and therapeutic resistance of multiple human cancers, including ATL, breast, colon and lung. Based on these innovative findings, we hypothesize that PDLIM2 repression leads to constitutive NF-?B activation, which in turn contributes to cancer pathogenesis and therapy resistance. In this application, we aim to (1) determine the molecular mechanisms by which PDLIM2 expression is repressed in lung cancer; (2) elucidate the mechanistic role of PDLIM2 in lung cancer development; and (3) examine the role and mechanisms of PDLIM2 in lung cancer chemosensitivity and therapy. These studies are innovative and significant, because they will greatly increase our understanding of the tumorigenesis and chemoresistance of lung cancer, and may form a novel class of PDLIM2-based epigenetic approaches as a primary or adjuvant therapy for lung cancer prevention and treatment. In particular, clinical trials show that it is impractical to block NF-?B activation for
cancer therapy using 'classical' NF-?B inhibitors because of the importance of NF-?B in human physiology. However, PDLIM2 prevents pathogenic but not physiological activation of NF-?B by terminating NF-?B activation. Consistently, PDLIM2 expression, although repressed in cancer cells, is high under physiological conditions. Thus, PDLIM2-based therapies will effectively alleviate NF-?B-mediated tumorigenesis and chemoresistance while keeping the physiological functions of NF-?B, such as immune responses, intact in patients. Moreover, it is feasible to target PDLIM2 for cancer therapy because our studies show that the repression of PDLIM2 expression in cancer cells is pharmacologically reversible.
描述(由申请人提供):化疗仍然是许多癌症的标准一线治疗,包括肺癌,肺癌是癌症死亡的主要原因,仅在美国每年就有大约160,000人死亡。然而,由于癌细胞的内在和获得性抗性,目前化疗的益处非常有限。我们研究的长期目标是了解肿瘤发生和化疗耐药性的机制,并将这种理解转化为新的方法,通过建立新的有效疗法和/或启动癌细胞对当前治疗药物的反应来提高癌症治愈率。为此,我们最近鉴定了PDLIM 2,一种在肺部表达水平最高的普遍表达的含PDZ-LIM结构域的蛋白,作为肺癌和其他几种癌症类型如成人T细胞白血病/淋巴瘤(ATL),乳腺癌和结肠癌的抑制因子。我们发现PDLIM 2的表达在这些癌细胞中受到表观遗传学抑制,并且PDLIM 2重建阻止了它们的致瘤性。此外,PDLIM 2缺陷使小鼠易患自发性和诱导性癌症,特别是肺癌。值得注意的是,PDLIM 2表达的抑制与肺癌的化疗耐药性相关,并且PDLIM 2再诱导是表观遗传药物5-aza-dC诱导多药耐药肺癌细胞中的生长抑制和对化疗药物卡铂的反应所必需的。 机制研究表明,PDLIM 2功能作为泛素E3连接酶选择性降解核(激活)NF-?B RelA(也称为p65),其是一种转录因子,已被认为在多种人类癌症(包括ATL、乳腺癌、结肠癌和肺癌)的肿瘤发生和治疗抗性中起致病作用。基于这些创新的发现,我们假设PDLIM 2抑制导致组成性NF-?B激活,这反过来又有助于癌症发病机制和治疗抗性。在本申请中,我们的目的是(1)确定PDLIM 2表达在肺癌中被抑制的分子机制;(2)阐明PDLIM 2在肺癌发展中的机制作用;(3)检查PDLIM 2在肺癌化疗敏感性和治疗中的作用和机制。 这些研究具有创新性和重要意义,因为它们将大大增加我们对肺癌的肿瘤发生和化疗耐药性的理解,并可能形成一类新的基于PDLIM 2的表观遗传方法,作为肺癌预防和治疗的主要或辅助治疗。特别是,临床试验表明,这是不切实际的,以阻止NF-?B激活
使用“经典”NF-?B抑制剂,因为NF-?人类生理学的B。然而,PDLIM 2阻止NF-?B终止NF-?B激活。 一致地,PDLIM 2表达,虽然在癌细胞中被抑制,但在生理条件下是高的。因此,PDLIM 2为基础的治疗将有效地减轻NF-?B介导的肿瘤发生和化疗耐药性,同时保持NF-?B,如免疫反应,在患者中完好无损。此外,靶向PDLIM 2用于癌症治疗是可行的,因为我们的研究表明癌细胞中PDLIM 2表达的抑制是可逆的。
项目成果
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{{ truncateString('GUTIAN XIAO', 18)}}的其他基金
PDLIM2 as a cancer and chemosensitizing target
PDLIM2 作为癌症和化疗增敏靶点
- 批准号:
9265025 - 财政年份:2013
- 资助金额:
$ 30.95万 - 项目类别:
PDLIM2 as a cancer and chemosensitizing target
PDLIM2 作为癌症和化疗增敏靶点
- 批准号:
8575709 - 财政年份:2013
- 资助金额:
$ 30.95万 - 项目类别:
HTLV deregulation of NF-kappaB2 p100 processing in tumor
HTLV 对肿瘤中 NF-kappaB2 p100 加工的失调
- 批准号:
7494730 - 财政年份:2006
- 资助金额:
$ 30.95万 - 项目类别:
HTLV deregulation of NF-kappaB2 p100 processing in tumor
HTLV 对肿瘤中 NF-kappaB2 p100 加工的失调
- 批准号:
7102359 - 财政年份:2006
- 资助金额:
$ 30.95万 - 项目类别:
HTLV deregulation of NF-kappaB2 p100 processing in tumor
HTLV 对肿瘤中 NF-kappaB2 p100 加工的失调
- 批准号:
7822944 - 财政年份:2006
- 资助金额:
$ 30.95万 - 项目类别:
HTLV deregulation of NF-kappaB2 p100 processing in tumor
HTLV 对肿瘤中 NF-kappaB2 p100 加工的失调
- 批准号:
7406605 - 财政年份:2006
- 资助金额:
$ 30.95万 - 项目类别:
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