Berberine downregulates MDM2 by interaction with DAXX in cancer cells

小檗碱通过与癌细胞中的 DAXX 相互作用下调 MDM2

• 批准号: 8599444
• 负责人: MUXIANG ZHOU
• 金额: $ 6.53万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-01 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8599444
• 关键词: Acute Lymphocytic Leukemia; Address; Alkaloids; Apoptosis; Apoptotic; Berberine; Biological Factors; Cancer Cell Growth; Cancer Patient; Cells; Childhood; Chinese People; Clinical; Clinical Trials; DAXX gene; Data; Development; Down-Regulation; Doxorubicin; Drug resistance; Future; Goals; Health; Human; Isoquinolines; Knowledge; MDM2 gene; Malignant Childhood Neoplasm; Malignant Neoplasms; Medicinal Herbs; Molecular; Neuroblastoma; Oncogene Proteins; Pathway interactions; Patients; Pharmaceutical Preparations; Play; Protein p53; Reagent; Refractory; Regulation; Resistance; Role; Testing; Therapeutic; Therapeutic Agents; Ubiquitination; Up-Regulation; anticancer activity; base; cancer cell; cancer initiation; cytotoxic; cytotoxicity; design; drug candidate; drug development; in vivo; innovation; killings; novel therapeutics; outcome forecast; overexpression; patient population; response; therapy resistant; ubiquitin-protein ligase

DESCRIPTION (provided by applicant): The multifunctional oncoprotein MDM2 plays critical roles in cancer initiation, progression and the development of resistance to therapy. We studied pediatric cancer patients, including those with acute lymphoblastic leukemia (ALL) and neuroblastoma (NB), finding that patients with a poor prognosis commonly had cancer cells that expressed constitutively high levels of MDM2. An important function of MDM2 is the ubiquitination (as an E3 ligase) and degradation of the tumor suppressor p53, due to interactions with DAXX and HAUSP. Interestingly, disruption of these interactions can result in self-ubiquitination of MDM2 and p53 activation. Thus, we believe targeting MDM2 by disrupting MDM2-DAXX-HAUSP interactions is an innovative approach to develop new therapeutics for MDM2-overexpressing cancer patients. Berberine (BBR), an isoquinoline alkaloid derived from a traditional Chinese medicinal herb, has been shown to have anti-proliferative and pro-apoptotic effects on human cancer. Our preliminary data supports a previously unrecognized mechanism of action for BBR: It downregulates MDM2 by inhibiting DAXX, disrupting MDM2-DAXX-HAUSP interactions. In contrast to the conventional chemotherapeutic drug doxorubicin (Dox) that induces prior p53 activation and a subsequent upregulation of MDM2, we discovered that BBR strongly induced persistent downregulation of MDM2, followed by a steady-state activation of p53, resulting in potent apoptosis of MDM2-overexpressing cancer cells, including those that are Dox-resistant. This proposal is designed to test our central hypothesis that regulation of MDM2 by DAXX inhibition is the major mechanism by which BBR differs from Dox in exerting its anti-cancer effect. The project's long term objectives are: characterization of the critical role BBR plays in the downregulation of MDM2 to overcome chemoresistance and determination of BBR's potential as a therapeutic reagent for refractory cancer patients. The specific aims of this study are: 1) To fully elucidate the cellular/molecular mechanisms by which BBR downregulates MDM2; 2) To establish that downregulation of MDM2 is the primary mechanism by which BBR exerts its anticancer effects; and 3) To assess the ability of BBR to reverse chemoresistance and its potential as a treatment for refractory cancer patients. Successful completion of these specific aims will generate knowledge with respect to the mechanisms of action for BBR prior to future clinical trials of this natural product in pediatric cancer patients, should introduce BBR as a highly useful new drug candidate for overcoming chemoresistance, and also will provide a basic framework for the rational design of other therapeutic approaches targeting the DAXX-MDM2 pathway.

描述（由申请人提供）：多功能癌蛋白MDM2在癌症的发生、进展和治疗耐药性的发展中发挥着关键作用。我们研究了儿童癌症患者，包括患有急性淋巴细胞白血病 (ALL) 和神经母细胞瘤 (NB) 的患者，发现预后不良的患者通常具有表达高水平 MDM2 的癌细胞。 MDM2 的一个重要功能是由于与 DAXX 和 HAUSP 的相互作用而泛素化（作为 E3 连接酶）和肿瘤抑制因子 p53 的降解。有趣的是，这些相互作用的破坏可能导致 MDM2 和 p53 激活的自我泛素化。因此，我们相信通过破坏 MDM2-DAXX-HAUSP 相互作用来靶向 MDM2 是为 MDM2 过表达癌症患者开发新疗法的创新方法。小檗碱 (BBR) 是一种从传统中草药中提取的异喹啉生物碱，已被证明对人类癌症具有抗增殖和促凋亡作用。我们的初步数据支持了 BBR 以前未被认识的作用机制：它通过抑制 DAXX、破坏 MDM2-DAXX-HAUSP 相互作用来下调 MDM2。与传统化疗药物阿霉素（Dox）诱导p53激活和随后MDM2上调相反，我们发现BBR强烈诱导MDM2持续下调，随后p53稳态激活，导致MDM2强效凋亡-过度表达癌细胞，包括那些对阿霉素具有抗药性的癌细胞。该提案旨在检验我们的中心假设，即通过 DAXX 抑制调节 MDM2 是 BBR 与 Dox 发挥抗癌作用的主要机制。该项目的长期目标是：表征 BBR 在下调 MDM2 以克服化疗耐药性方面所发挥的关键作用，并确定 BBR 作为难治性癌症患者治疗试剂的潜力。本研究的具体目的是：1）全面阐明BBR下调MDM2的细胞/分子机制； 2) 确立MDM2的下调是BBR发挥抗癌作用的主要机制； 3) 评估 BBR 逆转化疗耐药的能力及其作为难治性癌症患者治疗的潜力。成功完成这些具体目标将在未来对该天然产物在儿科癌症患者中进行临床试验之前产生有关 BBR 作用机制的知识，应将 BBR 作为克服化疗耐药性的非常有用的新候选药物引入，并且还将提供合理设计其他针对 DAXX-MDM2 通路的治疗方法的基本框架。