SESN2 and therapeutic effect of Isohapontigenin (ISO)

SESN2和异皂甙元（ISO）的治疗效果

基本信息

批准号：
10450132
负责人：
Max Costa
金额：
$ 41.36万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-02-01 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10450132
关键词：
Address Affect Anchorage-Independent Growth Apoptosis Apoptotic Autophagocytosis Biological Bladder Bladder Neoplasm Carcinogens Cells Cessation of life Chemicals Chemopreventive Agent Chinese Herbs Clinical Data Development Diagnosis Dose Epigenetic Process Epithelial Evaluation Event Exhibits Gnetum Goals Growth Herb Human In Vitro Life Malignant Neoplasms Malignant neoplasm of urinary bladder Mediating Metastatic Neoplasm to the Lung MicroRNAs Microarray Analysis Modeling Molecular Mus National Cancer Institute Neoplasm Metastasis Normal tissue morphology Nude Mice Pathway interactions Patient-Focused Outcomes Pharmaceutical Preparations Play Reporting Research Proposals Role Stilbenes Testing Therapeutic Therapeutic Effect Tissues Tumor Cell Invasion United States Up-Regulation anti-cancer anticancer activity base cancer cell carcinogenicity cell growth dosage genetic approach impaired capacity improved in vitro activity in vivo in vivo Model insight mortality mouse model neoplastic cell novel response success tumor tumor growth

项目摘要

Project Summary Human bladder cancer is the sixth most common cancer in the United States. Discovery and evaluation of new alternative medications is of tremendous importance for reducing the bladder cancer mortality. Chinese herb Gnetum Cleistostachyun has been used for treatment of bladder cancers for centuries, but its bioactive components and anti-cancer mechanisms have been barely explored. Our recent studies discovered that Isorhapontigenin (ISO), a new derivative of stilbene compound isolated from this herb, exhibited multiple anti- cancer activities in human high grade invasive bladder cancer cells. Our preliminary studies provided strong evidence on ISO inhibition of tumor growth both in vitro and in vivo. In addition, the robust induction of SESN2 and BECN1, the important autophagy regulator and effector, have been shown as a critical event for ISO's anti-cancer activity in vitro, as depletion of either SESN2 or BECN1 significantly impaired the capacity of ISO to inhibit tumor cell growth. However, many questions, such as whether ISO affects cell invasion and tumor metastasis in vivo, and whether SESN2/BECN1 mediates ISO's in vivo activity, as well as upstream regulators being responsible for their upregulation by ISO, remain unknown. Therefore, in this application, three specific aims were proposed to address key events in SESN2/BECN1-mediated ISO tumor inhibition. The first Aim will target the potential upstream regulators and epigenetic mechanism that mediate ISO-induced upregulation of SESN2 and BECN1. The second Aim will employ both in vitro and in vivo approaches to address the functional relevance of SESN2 and BECN1 as well as new candidates obtained from Aim 1 in ISO inhibition of tumor invasion and metastasis. The last Aim will focus on in vivo role of SESN2 and BECN1 in BC development using BBN-induced mouse bladder carcinogenic model. The results obtained from the proposed studies will determine whether ISO specifically initiates the SESN2/BECN1/autophagy pathway to inhibit bladder tumor formation, invasion, and metastasis. The success of this proposal will facilitate our understanding of the molecular basis of ISO anti-cancer activity and will also provide new insights for developing a better therapeutic strategy for human high grade invasive bladder cancer.

项目摘要人膀胱癌是美国第六大癌症。新发现和评估替代药物对于降低膀胱癌死亡率至关重要。中草药 gnetum cleistostachyun已用于治疗膀胱癌，但其生物活性几乎没有探索组件和抗癌机制。我们最近的研究发现异甲替尼蛋白（ISO），这是一种从这种草药中分离出的Stilbene化合物的新衍生物，表现出多种抗人类高级浸润性膀胱癌细胞中的癌症活性。我们的初步研究提供了很强的关于体外和体内肿瘤生长的ISO抑制作用的证据。另外，SESN2的稳健诱导重要的自噬调节器和效应子BecN1已被证明是ISO的关键事件体外抗癌活性，因为SESN2或BECN1的耗竭显着损害了ISO对抑制肿瘤细胞生长。但是，许多问题，例如ISO是否影响细胞侵袭和肿瘤体内转移，以及SESN2/BECN1是否介导ISO的体内活动以及上游调节剂负责他们的ISO上调，仍然未知。因此，在此应用中，三个特定提出目的是解决SESN2/BECN1介导的ISO肿瘤抑制中的关键事件。第一个目标靶向潜在的上游调节剂和表观遗传机制，该机制介导了ISO诱导的上调 SESN2和BECN1。第二个目标将采用体外和体内方法来解决该功能 SESN2和BECN1的相关性以及从AIM 1获得的新候选物在ISO抑制肿瘤中入侵和转移。最后一个目标将重点放在SESN2和BECN1在卑诗省开发中的体内作用使用BBN诱导的小鼠膀胱致癌模型。从拟议的研究中获得的结果将确定ISO是否专门启动SESN2/BECN1/自噬途径以抑制膀胱肿瘤形成，入侵和转移。该提案的成功将有助于我们理解 ISO抗癌活性的分子基础，还将提供新的见解，以开发更好人类高级侵入性膀胱癌的治疗策略。

项目成果

期刊论文数量（21）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Extracellular Vesicles as Mediators of Nickel-Induced Cancer Progression.

DOI：
10.3390/ijms232416111
发表时间：
2022-12-17
期刊：
International journal of molecular sciences
影响因子：
5.6
作者：
通讯作者：

NFκB2 p52 stabilizes rhogdiβ mRNA by inhibiting AUF1 protein degradation via a miR-145/Sp1/USP8-dependent axis.

NFκB2 p52 通过 miR-145/Sp1/USP8 依赖轴抑制 AUF1 蛋白降解来稳定 rhogdiβ mRNA。

DOI：
10.1002/mc.22970
发表时间：
2019
期刊：
Molecular carcinogenesis
影响因子：
4.6
作者：
Xu,Jiawei;Hua,Xiaohui;Jin,Honglei;Zhu,Junlan;Li,Yang;Li,Jingxia;Huang,Chuangshu
通讯作者：
Huang,Chuangshu

PHLPP2 stabilization by p27 mediates its inhibition of bladder cancer invasion by promoting autophagic degradation of MMP2 protein.

DOI：
10.1038/s41388-018-0374-1
发表时间：
2018-10
期刊：
Oncogene
影响因子：
8
作者：
Peng M;Wang J;Zhang D;Jin H;Li J;Wu XR;Huang C
通讯作者：
Huang C

New compound ChlA-F induces autophagy-dependent anti-cancer effect via upregulating Sestrin-2 in human bladder cancer.

DOI：
10.1016/j.canlet.2018.08.013
发表时间：
2018-11-01
期刊：
Cancer letters
影响因子：
9.7
作者：
Hua X;Xu J;Deng X;Xu J;Li J;Zhu DQ;Zhu J;Jin H;Tian Z;Huang H;Zhao QS;Huang C
通讯作者：
Huang C

Long Non-Coding RNA MEG3 in Metal Carcinogenesis.