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.
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.
|Jiang, Guosong; Wu, Amy D; Huang, Chao et al. (2016) Isorhapontigenin (ISO) Inhibits Invasive Bladder Cancer Formation In Vivo and Human Bladder Cancer Invasion In Vitro by Targeting STAT1/FOXO1 Axis. Cancer Prev Res (Phila) 9:567-80|
|Xu, Jiawei; Wang, Yulei; Hua, Xiaohui et al. (2016) Inhibition of PHLPP2/cyclin D1 protein translation contributes to the tumor suppressive effect of NFÎºB2 (p100). Oncotarget 7:34112-30|
|Zeng, Xingruo; Xu, Zhou; Gu, Jiayan et al. (2016) Induction of miR-137 by Isorhapontigenin (ISO) Directly Targets Sp1 Protein Translation and Mediates Its Anticancer Activity Both In Vitro and In Vivo. Mol Cancer Ther 15:512-22|
|Wang, Y; Xu, J; Gao, G et al. (2016) Tumor-suppressor NFÎºB2 p100 interacts with ERK2 and stabilizes PTEN mRNA via inhibition of miR-494. Oncogene 35:4080-90|
|Huang, Haishan; Pan, Xiaofu; Jin, Honglei et al. (2015) PHLPP2 Downregulation Contributes to Lung Carcinogenesis Following B[a]P/B[a]PDE Exposure. Clin Cancer Res 21:3783-93|
|Zhang, Dongyun; Liang, Yuguang; Xie, Qipeng et al. (2015) A novel post-translational modification of nucleolin, SUMOylation at Lys-294, mediates arsenite-induced cell death by regulating gadd45Î± mRNA stability. J Biol Chem 290:4784-800|
|Jin, Honglei; Yu, Yonghui; Hu, Young et al. (2015) Divergent behaviors and underlying mechanisms of cell migration and invasion in non-metastatic T24 and its metastatic derivative T24T bladder cancer cell lines. Oncotarget 6:522-36|
|Cao, Zipeng; Li, Xueyong; Li, Jingxia et al. (2014) X-linked inhibitor of apoptosis protein (XIAP) lacking RING domain localizes to the nuclear and promotes cancer cell anchorage-independent growth by targeting the E2F1/Cyclin E axis. Oncotarget 5:7126-37|
|Zhang, Ruowen; Wang, Yulei; Li, Jingxia et al. (2014) The Chinese herb isolate yuanhuacine (YHL-14) induces G2/M arrest in human cancer cells by up-regulating p21 protein expression through an p53 protein-independent cascade. J Biol Chem 289:6394-403|
|Zhang, Dongyun; Wang, Yulei; Liang, Yuguang et al. (2014) Loss of p27 upregulates MnSOD in a STAT3-dependent manner, disrupts intracellular redox activity and enhances cell migration. J Cell Sci 127:2920-33|
Showing the most recent 10 out of 27 publications