SESN2 and therapeutic effect of Isohapontigenin (ISO)

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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.