PS-341-induced Apoptosis in Squamous Cell Carcinoma

PS-341 诱导鳞状细胞癌细胞凋亡

• 批准号: 8240973
• 负责人: CUN-YU WANG
• 金额: $ 38.5万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-02-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8240973
• 关键词: Acetylation; Apoptosis; Apoptotic; Autophagocytosis; Basic Science; Bcl-2 Homology Domain; Biological Assay; Biological Models; Bortezomib; Cancer cell line; Caspase; Cell Death; Cell Line; Cell model; Cells; Chromatin Structure; Cisplatin; Clinical; Clinical Research; Diagnosis; Epigenetic Process; Exhibits; Flow Cytometry; Funding; Genes; Genetic Transcription; Goals; HDAC6 gene; Head and Neck Cancer; Head and Neck Squamous Cell Carcinoma; Head and neck structure; Heat shock proteins; Heat-Shock Response; Histone Deacetylase; Histone Deacetylase Inhibitor; Histone H3; Histones; Human; Hydroxamic Acids; In Vitro; Instruction; Lysine; Malignant Epithelial Cell; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Metabolic; Methylation; Molecular; Multiple Myeloma; Noxae; Nude Mice; Patients; Pharmaceutical Preparations; Process; Property; Proteasome Inhibitor; Proteins; Reporting; Research Personnel; Resistance; Reverse Transcriptase Polymerase Chain Reaction; Screening for cancer; Second Primary Cancers; Signal Pathway; Signal Transduction; Squamous cell carcinoma; Survival Rate; Testing; Therapeutic; Therapeutic Agents; Time; Tumor Suppressor Genes; Ubiquitination; Velcade; Western Blotting; Work; base; cancer cell; cancer therapy; cellular targeting; chemotherapeutic agent; chemotherapy; chromatin immunoprecipitation; conventional therapy; cytotoxicity; endoplasmic reticulum stress; gene induction; heat-shock factor 1; improved; in vivo; innovation; knock-down; malignant breast neoplasm; mouse model; novel; novel therapeutics; prevent; programs; protein expression; small hairpin RNA; transcription factor; tumor

The main objectives of this continuation application are to elucidate the molecular mechanisms by which TSA enhances apoptosis induced by the proteasome inhibitor PS-341 in head and neck squamous cell carcinoma (HNSCC) cells. During the last funding period, we found that the co-treatment of PS-341 and TSA in HNSCC cells synergistically induces apoptosis by increasing the expression of pro-apoptotic gene Noxa. To further understand the molecular mechanisms by which TSA enhances PS-341-induced apoptosis, we propose the following four specific aims: Aim 1 is to explore the epigenetic mechanisms by which PS- 341/TSA induce Noxa expression in HNSCC cells. We hypothesize PS-341/TSA may modify histone ubiquitination to promote Noxa expression in addition to histone accetylation. We will perform chromatin immunoprecipitation (ChIP) assay to determine how PS-341 modulates ubiquitination of H2A and promotes Noxa expression. Aim 2 is to determine whether TSA may enhance apoptosis by inhibiting autophagy formation in HNSCC cells. Based on our preliminary studies, we hypothesize that TSA may inhibit autophagy and heat shock responses by targeting cellular HDAC6. We will examine whether TSA reduces PS-341- induced autophagy, thereby enhancing apoptosis. We will examine whether TSA inhibits heat shock protein expression by targeting the transcription factor heat shock factor 1. Aim 3 is to determine whether PS- 341/TSA potently induce the apoptosis of cancer initiating cells (CICs) in vitro and in vivo. CICs exhibit an intrinsic resistance to chemotherapeutic agents, preventing complete elimination of the tumor. Paradoxically, CICs are difficult to maintain or propagate in vitro which represents a significant barrier to study CICs properties and to screen cancer therapeutic drugs against CICs. To overcome this barrier, we propose to develop a cell model system to study CICs from human HNSCC cell lines. We will examine whether PS- 341/TSA can potently induce apoptosis of CICs in vitro and in vivo. Aim 4 is to explore whether and how Hippo-YAP signaling modulates PS-341/TSA-induced apoptosis. We will over-express or knock-down YAP in HNSCC cells to determine how YAP modulates PS-341/TSA-induced apoptosis. Our work may help to develop targeting therapy for HNSCC with abnormal activation of YAP signaling. In summary, new findings from this application will have clinical implications for treating HNSCC and may help to develop innovative strategies for human cancer treatment RELEVANCE (See instructions): Head and neck cancer typically presents as a very malignant tumor and is frequently resistant to chemo- therapy. The major goals of this project are to develop new therapy strategies for treating head and neck cancer and to improve efficacy of chemotherapy.

该延续应用的主要目标是阐明分子机制 TSA增强了蛋白酶体抑制剂PS-341在头部和颈部鳞状细胞中诱导的凋亡 癌（HNSCC）细胞。在最后的资金期间，我们发现PS-341和TSA的共同处理 在HNSCC细胞中，通过增加凋亡基因NOXA的表达来协同诱导凋亡。 为了进一步了解TSA增强PS-341诱导凋亡的分子机制，我们 提出以下四个特定目标：目标1是探索PS-的表观遗传机制 341/TSA在HNSCC细胞中诱导NOXA表达。我们假设PS-341/TSA可能会改变组蛋白 除组蛋白加速外，泛素化以促进NOXA表达。我们将执行染色质 免疫沉淀（芯片）测定法确定PS-341如何调节H2A的泛素化并促进 NOXA表达。 AIM 2是确定TSA是否可以通过抑制自噬来增强凋亡 HNSCC细胞中的形成。根据我们的初步研究，我们假设TSA可能会抑制自噬 通过靶向细胞HDAC6来产生热激反应。我们将检查TSA是否减少PS-341-- 诱导自噬，从而增强凋亡。我们将检查TSA是否抑制热激蛋白 通过靶向转录因子热休克因子1的表达。目标3是确定PS-是否是否 341/TSA有效地诱导癌症引发细胞（CICS）的凋亡，体外和体内。 CICS展出 对化学治疗剂的内在耐药性，以防止完全消除肿瘤。矛盾的是， CIC难以维持或在体外传播，这代表了研究CIC的重大障碍 特性和针对CICS筛查癌症治疗药物。为了克服这一障碍，我们建议 开发一个细胞模型系统来研究人类HNSCC细胞系的CIC。我们将检查PS-是否 341/TSA可以在体外和体内有效诱导CICS的凋亡。目标4是探索是否以及如何 Hippo-YAP信号传导调节PS-341/TSA诱导的凋亡。我们将过分表达或击倒yap 在HNSCC细胞中，以确定YAP如何调节PS-341/TSA诱导的凋亡。我们的工作可能有助于 开发针对HNSCC的靶向治疗，并具有异常激活YAP信号传导。总之，新发现 通过此应用程序将对治疗HNSCC具有临床意义，并可能有助于开发创新 人类癌症治疗策略 相关性（请参阅说明）： 头颈癌通常是一种非常恶性的肿瘤，并且经常对化学性抗性 治疗。该项目的主要目标是制定新的治疗策略来治疗头部和颈部 癌症并提高化学疗法的功效。