SESN2 and therapeutic effect of Isohapontigenin (ISO)

项目摘要 人类膀胱癌是美国第六大常见癌症。发现和评价新的 替代性药物治疗对于降低膀胱癌死亡率是非常重要的。中药 买麻藤隐穗花已被用于治疗膀胱癌几个世纪，但其生物活性， 成分和抗癌机制几乎没有探索。我们最近的研究发现， 异甘草素（Isorhapontigenin，ISO）是从该植物中分离得到的一种新的二苯乙烯类化合物，具有多种抗肿瘤活性， 人高级别浸润性膀胱癌细胞的癌症活性。我们的初步研究提供了强大的 ISO在体外和体内抑制肿瘤生长的证据。此外，SESN 2的稳健诱导 BECN 1是重要的自噬调节因子和效应因子，已被证明是ISO的关键事件。 体外抗癌活性，因为SESN 2或BECN 1的缺失显著损害了ISO的能力， 抑制肿瘤细胞生长。然而，许多问题，如ISO是否影响细胞侵袭和肿瘤 体内转移，以及SESN 2/BECN 1是否介导ISO的体内活性，以及上游调节因子 负责他们的上调ISO，仍然未知。因此，在本申请中， 目的是解决SESN 2/BECN 1介导的ISO肿瘤抑制中的关键事件。第一个目标将 靶向潜在的上游调节因子和介导ISO诱导的上调的表观遗传机制， SESN 2和BECN 1。第二个目标将采用体外和体内方法来解决功能性 SESN 2和BECN 1以及从Aim 1获得的新候选物在肿瘤的ISO抑制中的相关性 侵袭和转移。最后一个目标将集中在SESN 2和BECN 1在BC发展中的体内作用 采用BBN诱导的小鼠膀胱癌模型。从拟议研究中获得的结果将 确定ISO是否特异性地启动SESN 2/BECN 1/自噬途径以抑制膀胱肿瘤 形成、侵袭和转移。这一建议的成功将有助于我们了解 ISO抗癌活性的分子基础，也将为开发更好的 人高级别浸润性膀胱癌的治疗策略。

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.