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: 8403808
• 负责人: MUXIANG ZHOU
• 金额: $ 29.33万
• 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 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8403808
• 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）：多功能肿瘤蛋白MDM2在癌症的发生、进展和耐药发展中起关键作用。我们研究了儿童癌症患者，包括急性淋巴细胞白血病（ALL）和神经母细胞瘤（NB）患者，发现预后不良的患者通常有表达组成性高水平MDM2的癌细胞。MDM2的一个重要功能是泛素化（作为E3连接酶）和肿瘤抑制因子p53的降解，这是由于与DAXX和HAUSP的相互作用。有趣的是，这些相互作用的破坏可导致MDM2的自泛素化和p53的激活。因此，我们相信通过破坏MDM2- daxx - hausp相互作用来靶向MDM2是一种创新的方法，可以为MDM2过表达的癌症患者开发新的治疗方法。小檗碱（Berberine， 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的作用。我们的初步数据支持了先前未被认识的BBR的作用机制：它通过抑制DAXX来下调MDM2，破坏MDM2-DAXX- hausp的相互作用。与传统化疗药物多柔比星（Dox）诱导p53激活和随后的MDM2上调不同，我们发现BBR强烈诱导MDM2持续下调，随后是p53的稳态激活，导致MDM2过表达的癌细胞（包括那些对Dox耐药的癌细胞）的有效凋亡。本研究旨在验证我们的中心假设，即DAXX抑制对MDM2的调节是BBR不同于Dox发挥抗癌作用的主要机制。该项目的长期目标是：确定BBR在MDM2下调以克服化疗耐药中所起的关键作用，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)确立了MDM2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治疗难治性癌症患者的潜力。这些特定目标的成功完成将为未来在儿童癌症患者中进行天然产物的临床试验提供有关BBR作用机制的知识，将BBR作为克服化疗耐药的非常有用的新候选药物引入，并将为合理设计其他靶向DAXX-MDM2途径的治疗方法提供基本框架。