Urothelial carcinoma of the bladder (or bladder cancer, BC) is one of the most common cancers in the Western world. Because high-grade invasive bladder cancers (HGIBC) can progress to life threatening metastases, identifying a natural compound that specifically inhibits BC invasion and metastasis is of tremendous importance for potentially reducing mortality as a result of this disease. Isorhapontigenin (ISO) i a new derivative of stilbene, and isolated from a Chinese herb that has been used in China for treatment of BCs for hundreds of years without understanding of molecular mechanisms. Thus, the goal of this proposal is to determine the ISO potential therapeutic effect and the molecular mechanisms responsible for this anti-cancer activity. Our preliminary studies found that the X-linked inhibitor of the apoptosis protein (XIAP) was extremely highly expressed in all of the human invasive BC tissues that were tested, but it was barely detectable in all adjacent normal bladder tissues, and that XIAP expression level was also markedly elevated in BBN-induced invasive BC tissues in p53-/-/pRb-/- mice as compared with that from wild-type mice and oncogenic Ras- induced low-grade BCs. We also found that XIAP was significantly higher in cultured human BC cells derived from HGIBC than from those derived from low-grade papillary bladder tumors (LGPBT). Moreover, we showed that treatment of BC cells with ISO inhibited HGIBC T24T cell migration and invasion, was accompanied with specific inhibition of Sp-1 transactivation and XIAP downregulation at the transcription level without affecting cell proliferation at doses of 5-10 M. Thus, we hypothesize that ISO is an effective therapeutic agent for the inhibition of BC invasion in vitro and BC invasion and metastasis in vivo via downregulation of the Sp-1/XIAP pathway. We will test this with the following aims: 1: To test the hypothesis that XIAP downregulation by ISO is responsible for its inhibition of BBN-induced BC formation in the mice lacking both p53 and pRb; 2: To evaluate the hypothesis that SP-1 is a major target for ISO downregulation of XIAP in BC in vitro and in vivo; 3: To define the molecular mechanisms whereby ISO inhibits the BC development in vitro and in vivo. Success of the proposal will facilitate our understanding of the molecular mechanism(s) responsible for the anti-cancer effects of ISO compound. This novel finding will provide valuable information for the design of more effective strategies for utilization of ISO or for the synthesis of other novel conformation- constrained derivatives for the treatment of BCs and other cancers. Taken together with the fact that BC is the most common malignant tumors, responsible for 336,000 new cases and 132,000 deaths annually worldwide, the studies should in turn help improve the clinical outcome of patients with BCs.

Public Health Relevance

Urothelial carcinoma of the bladder (or bladder cancer, BC) is one of the most common cancers in the Western world. Isorhapontigenin (ISO) is a new derivative of stilbene that has been isolated from the Gnetum Hainanense, a Chinese herb that has been used in China for treatment of BCs for hundreds of years without understanding of molecular mechanisms. Based on our preliminary studies, this proposal is to test the hypothesis that downregulation of X-linked inhibitor of apoptosis protein (XIAP) is responsible for the ISO therapeutic effect on BCs by mediating apoptosis and inhibiting cell migration. The significance of the studies proposed in this grant lies in identifying ISO as a mechanism-based anti-cancer novel agent against invasive BCs and providing a basis for possible clinical trials exploring the usefulness of ISO or other novel conformation-constrained derivatives as a promised agent against BCs in humans.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
4R01CA177665-03
Application #
8844225
Study Section
Chemo/Dietary Prevention Study Section (CDP)
Program Officer
Forry, Suzanne L
Project Start
2013-07-01
Project End
2019-04-30
Budget Start
2016-05-01
Budget End
2017-04-30
Support Year
3
Fiscal Year
2016
Total Cost
Indirect Cost
Name
New York University
Department
Public Health & Prev Medicine
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016
Huang, Chao; Zeng, Xingruo; Jiang, Guosong et al. (2017) XIAP BIR domain suppresses miR-200a expression and subsequently promotes EGFR protein translation and anchorage-independent growth of bladder cancer cell. J Hematol Oncol 10:6
Jin, Honglei; Xie, Qipeng; Guo, Xirui et al. (2017) p63? protein up-regulates heat shock protein 70 expression via E2F1 transcription factor 1, promoting Wasf3/Wave3/MMP9 signaling and bladder cancer invasion. J Biol Chem 292:15952-15963
Jiang, Guosong; Huang, Chao; Li, Jingxia et al. (2017) Role of STAT3 and FOXO1 in the Divergent Therapeutic Responses of Non-metastatic and Metastatic Bladder Cancer Cells to miR-145. Mol Cancer Ther 16:924-935
Zhu, Junlan; Li, Yang; Tian, Zhongxian et al. (2017) ATG7 Overexpression Is Crucial for Tumorigenic Growth of Bladder Cancer In Vitro and In Vivo by Targeting the ETS2/miRNA196b/FOXO1/p27 Axis. Mol Ther Nucleic Acids 7:299-313
Huang, Haishan; Jin, Honglei; Zhao, Huirong et al. (2017) RhoGDI? promotes Sp1/MMP-2 expression and bladder cancer invasion through perturbing miR-200c-targeted JNK2 protein translation. Mol Oncol 11:1579-1594
Zhou, C; Huang, C; Wang, J et al. (2017) LncRNA MEG3 downregulation mediated by DNMT3b contributes to nickel malignant transformation of human bronchial epithelial cells via modulating PHLPP1 transcription and HIF-1? translation. Oncogene 36:3878-3889
Yu, Yonghui; Jin, Honglei; Xu, Jiheng et al. (2017) XIAP overexpression promotes bladder cancer invasion in vitro and lung metastasis in vivo via enhancing nucleolin-mediated Rho-GDI? mRNA stability. Int J Cancer :
Jin, Honglei; Xu, Jiheng; Guo, Xirui et al. (2016) XIAP RING domain mediates miR-4295 expression and subsequently inhibiting p63? protein translation and promoting transformation of bladder epithelial cells. Oncotarget 7:56540-56557
Xu, Zhou; Zeng, Xingruo; Xu, Jiawei et al. (2016) Isorhapontigenin suppresses growth of patient-derived glioblastoma spheres through regulating miR-145/SOX2/cyclin D1 axis. Neuro Oncol 18:830-9
Wang, Y; Xu, J; Gao, G et al. (2016) Tumor-suppressor NF?B2 p100 interacts with ERK2 and stabilizes PTEN mRNA via inhibition of miR-494. Oncogene 35:4080-90

Showing the most recent 10 out of 38 publications