Mechanisms of MEK/ERK growth arrest signaling

MEK/ERK 生长抑制信号传导机制

• 批准号: 9759770
• 负责人: Jong-In Park
• 金额: $ 33.61万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-22 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9759770
• 关键词: Adenine Nucleotide Translocase; Advanced Development; Bioenergetics; Bypass; Cancer Biology; Cause of Death; Cell Death; Cell Membrane Permeability; Cell Proliferation; Cell Survival; Cessation of life; Data; Doxycycline; Drug resistance; Energy Metabolism; Exhibits; Feedback; Funding; GRP75; Goals; Growth; Heat-Shock Proteins 70; Human; Link; MAP2K1 gene; MEKs; Malignant Neoplasms; Mediating; Metabolic; Mitochondria; Molecular; Molecular Chaperones; Mus; Mutation; Oncogenic; Pathway interactions; Permeability; Physiological; Proteins; Proteomics; Ras/Raf; Reporting; Research; Resistance; Signal Pathway; Signal Transduction; Stress; Testing; Therapeutic; Translating; Translations; Tumor Cell Line; Tumor Suppression; Up-Regulation; Voltage-Dependent Anion Channel; Xenograft procedure; base; cancer cell; cell transformation; deprivation; experimental study; improved; in vivo; inhibitor/antagonist; melanoma; mitochondrial membrane; mortalin; mutant; neoplastic cell; novel strategies; pancreatic cancer patients; screening; small hairpin RNA; small molecule inhibitor; stress tolerance; targeted treatment; tumor; tumorigenic

The Raf/MEK/ERK pathway is frequently deregulated in cancer, thus being a key target for therapy. Although recent development of advanced inhibitors targeting B-Raf and MEK1/2 has improved therapy of B-RafV600E,K melanoma, the ability of these tumors to develop drug resistance and the intrinsic resistance of many other MEK/ERK-deregulated tumor types to these inhibitors demand additional therapeutic strategies. Because tumor cells have the ability to develop drug resistances by reactivating MEK/ERK via genetic alterations or feedback rearrangement of the associated signaling network, it is predicted that current therapeutic strategies aiming MEK/ERK inhibition will be continuously challenged. Given that, one promising strategy would be to exploit a weakness(s) of cancer cells, which is inevitably associated with their aberrant MEK/ERK activity. The goal of this project is to determine whether mortalin (GRP75/HSPA9), a molecular chaperone in the HSP70 family, can be targeted to selectively induce mitochondria-driven death mechanisms in MEK/ERK-deregulated tumor cells. In the previous funding period, we discovered that mortalin upregulation in cancer is a key mechanism that facilitates MEK/ERK-mediated tumor cell proliferative signaling by suppressing the pathway’s potential to trigger growth arrest. In an effort to further elaborate mortalin functions in cancer, we discovered that mortalin can also facilitate tumor cell survival by regulating mitochondrial bioenergetics. This latter function of mortalin needs to be thoroughly evaluated in the context of MEK/ERK signaling because the data from our preliminary studies strongly suggest that mortalin deprivation can selectively induce robust cell death in tumor cells exhibiting aberrant MEK/ERK activity, including the B-RafV600E tumor cells that have acquired resistance to B-Raf inhibitors. Moreover, our data suggest that mortalin depletion induces cell death in MEK/ERK-deregulated tumor cells by regulating adenine nucleotide translocases (ANT) and voltage-dependent anion channel (VDAC), the mitochondrial channels that are critical for cellular bioenergetics but can also turn into powerful death machinery when stressed. We therefore hypothesize that a key function of mortalin is to protect tumor cells from mitochondrial bioenergetics stress caused by aberrant MEK/ERK activity. By extension, we predict that mortalin provides a unique target to selectively trigger mitochondrial death mechanisms in MEK/ERK- deregulated tumor cells. To test these hypotheses, Aim 1 will determine whether mortalin regulates cell death/survival via ANT/VDAC-associated mitochondrial permeability transition and Ca2+ flux from ER to mitochondria. Aim 2 will determine whether mortalin suppresses mitochondrial cell death caused by bioenergetics stress in MEK/ERK-deregulated tumor cells. Aim 3 will determine whether mortalin targeting can effectively suppress MEK/ERK-deregulated tumors in vivo. The obtained results will help define how mortain promotes survival and proliferation of MEK/ERK-deregulated cancers.

Raf/MEK/ERK通路在癌症中经常失调，因此是治疗的关键靶点。 尽管最近开发的靶向B-Raf和MEK 1/2的高级抑制剂改善了对肿瘤的治疗， B-RafV 600 E、K黑色素瘤、这些肿瘤产生耐药性的能力以及 这些抑制剂的许多其它MEK/ERK失调的肿瘤类型需要另外的治疗策略。 由于肿瘤细胞具有通过遗传途径重新激活MEK/ERK而产生耐药性的能力， 由于相关联的信令网络的改变或反馈重新布置，预测当前的信令网络将被重新配置。 针对MEK/ERK抑制的治疗策略将不断受到挑战。鉴于此，一个有希望的 一种策略是利用癌细胞的弱点，这不可避免地与它们的异常有关。 MEK/ERK活性。本项目的目标是确定是否mortalin（GRP 75/HSPA 9），一种分子 HSP 70家族中的分子伴侣，可以靶向选择性地诱导细胞死亡 MEK/ERK失调的肿瘤细胞中的机制。在上一个融资期，我们发现， 肿瘤中死亡蛋白上调是促进MEK/ERK介导的肿瘤细胞凋亡的关键机制。 通过抑制该途径触发生长停滞的潜力来抑制增殖信号传导。为努力进一步 通过详细阐述mortalin在癌症中的功能，我们发现mortalin还可以通过以下方式促进肿瘤细胞的存活： 调节线粒体生物能量学。死亡蛋白的后一种功能需要彻底评估， MEK/ERK信号传导的背景，因为我们初步研究的数据强烈表明， 死亡蛋白剥夺可以选择性地诱导表现出异常MEK/ERK的肿瘤细胞的强烈细胞死亡 活性，包括对B-Raf抑制剂具有获得性抗性的B-RafV 600 E肿瘤细胞。而且我们 数据表明，死亡蛋白耗竭通过调节MEK/ERK失调的肿瘤细胞中的细胞死亡， 腺嘌呤核苷酸移位酶（ANT）和电压依赖性阴离子通道（VDAC），线粒体 这些通道对细胞生物能量学至关重要，但也可以变成强大的死亡机器， 压力很大因此，我们假设死亡蛋白的一个关键功能是保护肿瘤细胞免受 线粒体生物能量学应激由异常的MEK/ERK活性引起。通过扩展，我们预测， mortalin提供了一个独特的目标，选择性地触发线粒体死亡机制，在MEK/ERK- 去调节的肿瘤细胞。为了验证这些假设，目标1将确定死亡蛋白是否调节细胞凋亡， 通过ANT/VDAC相关的线粒体渗透性转换和Ca 2+从ER到 线粒体目的2将确定死亡蛋白是否抑制线粒体细胞死亡引起的 MEK/ERK失调的肿瘤细胞中的生物能量学应激。AIM 3将决定死亡素是否 能有效抑制体内MEK/ERK失调的肿瘤。获得的结果将有助于确定如何 莫尔坦促进MEK/ERK失调的癌症的存活和增殖。