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途径经常在癌症中放松管制，因此是治疗的关键靶标。 尽管靶向B-RAF和MEK1/2的高级抑制剂的最新发展已改善 B-RAFV600E，K黑色素瘤，这些肿瘤发展耐药性和内在抗性的能力 这些抑制剂的许多其他MEK/ERK受管肿瘤类型都需要其他治疗策略。 因为肿瘤细胞具有通过遗传重新激活MEK/ERK来发展耐药性的能力 相关信号网络的更改或反馈重排，可以预测 瞄准MEK/ERK抑制的治疗策略将不断受到挑战。鉴于这一点，有人答应了 策略将是利用癌细胞的弱点，这与它们的异常不可避免地相关 MEK/ERK活动。该项目的目的是确定Mortalin（GRP75/HSPA9）是否是分子 HSP70家族中的伴侣可以有选择地诱导线粒体驱动的死亡 MEK/ERK受管肿瘤细胞中的机制。在上一个资金期间，我们发现 癌症中的Mortalin上调是促进MEK/ERK介导的肿瘤细胞的关键机制 通过抑制途径触发生长停滞的潜力来扩散信号传导。为了进一步 精致的Mortalin在癌症中的功能，我们发现Mortalin还可以通过 调节线粒体生物能学。莫塔林的以后功能需要在 MEK/ERK信令的背景是因为我们初步研究的数据强烈表明 洛尔替林的剥夺可以选择性地诱导表现出异常MEK/ERK的肿瘤细胞中稳健的细胞死亡 活性，包括对B-RAF抑制剂抗性的B-RAFV600E肿瘤细胞。而且，我们的 数据表明，Mortalin耗竭通过调节诱导MEK/ERK受控的肿瘤细胞的细胞死亡 腺嘌呤核苷酸易位酶（ANT）和电压依赖性阴离子通道（VDAC），线粒体 对于蜂窝生物能学至关重要的频道，但当当 强调。因此，我们假设Mortalin的关键功能是保护肿瘤细胞免受 由异常MEK/ERK活性引起的线粒体生物能胁迫。通过扩展，我们预测 Mortalin提供了一个独特的目标，可以选择性地触发MEK/ERK-的线粒体死亡机制 放松管制的肿瘤细胞。为了检验这些假设，AIM 1将确定Mortalin是否调节细胞 通过ANT/VDAC相关的线粒体通透性过渡和Ca2+通量从ER到ER的死亡/生存率 线粒体。 AIM 2将确定Mortalin是否抑制了由 MEK/ERK受控的肿瘤细胞中的生物能胁迫。 AIM 3将确定Mortalin是否针对 可以有效抑制体内MEK/ERK受控的肿瘤。获得的结果将有助于定义 Mortain促进MEK/ERK-DERETHECH癌的生存和增殖。