Mechanisms of MEK/ERK growth arrest signaling

MEK/ERK 生长抑制信号传导机制

基本信息

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
项目类别：
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

项目摘要

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，因此成为治疗的关键靶点。尽管最近针对 B-Raf 和 MEK1/2 的先进抑制剂的开发改善了治疗 B-RafV600E，K 黑色素瘤，这些肿瘤产生耐药性的能力和内在耐药性许多其他 MEK/ERK 失调的肿瘤类型需要这些抑制剂额外的治疗策略。因为肿瘤细胞有能力通过基因重新激活 MEK/ERK 来产生耐药性。相关信号网络的改变或反馈重新排列，预测当前鉴于此，针对 MEK/ERK 抑制的治疗策略将不断受到挑战。策略是利用癌细胞的弱点，这不可避免地与其异常相关该项目的目标是确定 mortalin (GRP75/HSPA9) 是否是一种分子。 HSP70 家族中的分子伴侣，可选择性诱导线粒体驱动的死亡 MEK/ERK 失调的肿瘤细胞中的机制在之前的资助期间，我们发现了这一点。癌症中mortalin上调是促进MEK/ERK介导的肿瘤细胞生长的关键机制通过抑制该途径引发生长停滞的潜力来抑制增殖信号。详细阐述了 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存活：调节线粒体生物能量学需要对 mortalin 的后一种功能进行彻底评估。 MEK/ERK 信号传导的背景，因为我们的初步研究数据强烈表明 mortalin 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，包括已获得对 B-Raf 抑制剂耐药性的 B-RafV600E 肿瘤细胞。数据表明，mortalin 耗竭通过调节 MEK/ERK 失调的肿瘤细胞诱导细胞死亡腺嘌呤核苷酸转位酶 (ANT) 和电压依赖性阴离子通道 (VDAC) 对细胞生物能量至关重要的通道，但也可以变成强大的死亡机器因此，我们认为 Mortalin 的一个关键功能是保护肿瘤细胞免受侵害。由异常 MEK/ERK 活性引起的线粒体生物能量应激通过扩展，我们预测。 mortalin 提供了一个独特的靶点来选择性触发 MEK/ERK- 中的线粒体死亡机制为了检验这些假设，目标 1 将确定 mortalin 是否调节细胞。通过 ANT/VDAC 相关的线粒体通透性转变和从 ER 到 Ca2+ 的 Ca2+ 通量来确定死亡/存活目标 2 将确定 mortalin 是否抑制由线粒体引起的细胞死亡。 MEK/ERK 失调的肿瘤细胞中的生物能应激将决定 Mortalin 是否靶向。可以有效地抑制体内 MEK/ERK 失调的肿瘤。所获得的结果将有助于确定如何抑制 MEK/ERK 失调的肿瘤。 mortain 促进 MEK/ERK 失调的癌症的存活和增殖。