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760 results on '"Wang, Junjian"'

1. Tumor mitochondrial oxidative phosphorylation stimulated by the nuclear receptor RORγ represents an effective therapeutic opportunity in osteosarcoma.

Author

Zheng, Jianwei, Wang, Qianqian, Chen, Jianghe, Cai, Guodi, Zhang, Zhenhua, Zou, Hongye, Zou, June, Liu, Qianqian, Ji, Shufeng, Shao, Guoli, Li, Hong, Li, Sheng, Chen, Hongwu, Lu, LinLin, Yuan, Yanqiu, Liu, Peiqing, and Wang, Junjian

Subjects
Osteosarcoma, Humans, Oxidative Phosphorylation, Mitochondria, Nuclear Receptor Subfamily 1, Group F, Member 3, Cell Line, Tumor, Animals, Bone Neoplasms, Mice, Reactive Oxygen Species, Apoptosis, Gene Expression Regulation, Neoplastic, Ferroptosis, Mice, Nude, Male, Cell Proliferation, RNA-Binding Proteins
Abstract

Osteosarcoma (OS) is the most common malignant bone tumor with a poor prognosis. Here, we show that the nuclear receptor RORγ may serve as a potential therapeutic target in OS. OS exhibits a hyperactivated oxidative phosphorylation (OXPHOS) program, which fuels the carbon source to promote tumor progression. We found that RORγ is overexpressed in OS tumors and is linked to hyperactivated OXPHOS. RORγ induces the expression of PGC-1β and physically interacts with it to activate the OXPHOS program by upregulating the expression of respiratory chain component genes. Inhibition of RORγ strongly inhibits OXPHOS activation, downregulates mitochondrial functions, and increases ROS production, which results in OS cell apoptosis and ferroptosis. RORγ inverse agonists strongly suppressed OS tumor growth and progression and sensitized OS tumors to chemotherapy. Taken together, our results indicate that RORγ is a critical regulator of the OXPHOS program in OS and provides an effective therapeutic strategy for this deadly disease.

Published
2024

7. Discovery of a highly potent and orally available importin-β1 inhibitor that overcomes enzalutamide-resistance in advanced prostate cancer.

Author

Huang, Jia-Luo, Yan, Xue-Long, Huang, Dong, Gan, Lu, Gao, Huahua, Fan, Run-Zhu, Li, Shen, Yuan, Fang-Yu, Zhu, Xinying, Tang, Gui-Hua, Wang, Junjian, Yin, Sheng, and Chen, Hongwu

Subjects
CRPC, Cancer, Daphnane diterpenoid, Drug discovery, Enzalutamide-resistance, Importin-β1, Natural product, Nuclear transporter
Abstract

Nuclear transporter importin-β1 is emerging as an attractive target by virtue of its prevalence in many cancers. However, the lack of druggable inhibitors restricts its therapeutic proof of concept. In the present work, we optimized a natural importin-β1 inhibitor DD1 to afford an improved analog DD1-Br with better tolerability (>25 folds) and oral bioavailability. DD1-Br inhibited the survival of castration-resistant prostate cancer (CRPC) cells with sub-nanomolar potency and completely prevented tumor growth in resistant CRPC models both in monotherapy (0.5 mg/kg) and in enzalutamide-combination therapy. Mechanistic study revealed that by targeting importin-β1, DD1-Br markedly inhibited the nuclear accumulation of multiple CRPC drivers, particularly AR-V7, a main contributor to enzalutamide resistance, leading to the integral suppression of downstream oncogenic signaling. This study provides a promising lead for CRPC and demonstrates the potential of overcoming drug resistance in advanced CRPC via targeting importin-β1.

Published
2023

9. Proteomic landscape of epithelial ovarian cancer

Author

Qian, Liujia, Zhu, Jianqing, Xue, Zhangzhi, Zhou, Yan, Xiang, Nan, Xu, Hong, Sun, Rui, Gong, Wangang, Cai, Xue, Sun, Lu, Ge, Weigang, Liu, Yufeng, Su, Ying, Lin, Wangmin, Zhan, Yuecheng, Wang, Junjian, Song, Shuang, Yi, Xiao, Ni, Maowei, Zhu, Yi, Hua, Yuejin, Zheng, Zhiguo, and Guo, Tiannan

Published
2024
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20. Nuclear TIGAR mediates an epigenetic and metabolic autoregulatory loop via NRF2 in cancer therapeutic resistance

Author

Wang, Hong, Wang, Qianqian, Cai, Guodi, Duan, Zhijian, Nugent, Zoann, Huang, Jie, Zheng, Jianwei, Borowsky, Alexander D, Li, Jian Jian, Liu, Peiqing, Kung, Hsing-Jien, Murphy, Leigh, Chen, Hong-Wu, and Wang, Junjian

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Cancer, Genetics, Biotechnology, Development of treatments and therapeutic interventions, 5.1 Pharmaceuticals, TIGAR, NSD2, NRF2, Metabolism, Oxidative stress, Epigenetic reprogramming, Therapeutic resistance, Redox homeostasis, ARE, antioxidant response element, DoxR, doxorubicin resistant, F2, 6bPase, fructose-2, 6-bisphosphatase, FBS, fetal bovine serum, NLS, nuclear localization signal, NRF2, NF-E2-related factor-2, NSCLC, non-small-cell lung carcinoma, NSD2, nuclear receptor binding SET domain protein 2, PGC1α, PPARG coactivator 1 alpha, PPP, pentose phosphate pathway, RadR, ionizing radiation-resistance, TIGAR, TP53-induced glycolysis and apoptosis regulator, TamR, tamoxifen resistant, Pharmacology and pharmaceutical sciences
Abstract

Metabolic and epigenetic reprogramming play important roles in cancer therapeutic resistance. However, their interplays are poorly understood. We report here that elevated TIGAR (TP53-induced glycolysis and apoptosis regulator), an antioxidant and glucose metabolic regulator and a target of oncogenic histone methyltransferase NSD2 (nuclear receptor binding SET domain protein 2), is mainly localized in the nucleus of therapeutic resistant tumor cells where it stimulates NSD2 expression and elevates global H3K36me2 mark. Mechanistically, TIGAR directly interacts with the antioxidant master regulator NRF2 and facilitates chromatin recruitment of NRF2, H3K4me3 methylase MLL1 and elongating Pol-II to stimulate the expression of both new (NSD2) and established (NQO1/2, PRDX1 and GSTM4) targets of NRF2, independent of its enzymatic activity. Nuclear TIGAR confers cancer cell resistance to chemotherapy and hormonal therapy in vitro and in tumors through effective maintenance of redox homeostasis. In addition, nuclear accumulation of TIGAR is positively associated with NSD2 expression in clinical tumors and strongly correlated with poor survival. These findings define a nuclear TIGAR-mediated epigenetic autoregulatory loop in redox rebalance for tumor therapeutic resistance.

Published
2022

32. Targeting Feedforward Loops Formed by Nuclear Receptor RORγ and Kinase PBK in mCRPC with Hyperactive AR Signaling.

Author

Zhang, Xiong, Huang, Zenghong, Wang, Junjian, Ma, Zhao, Yang, Joy, Corey, Eva, Evans, Christopher P, Yu, Ai-Ming, and Chen, Hong-Wu

Subjects
AR, AR-V7, CRPC, EMT, PBK, PDX, RORγ, antagonists, cell invasion, inverse agonists, kinase, metastasis, ROR&#947, Oncology and Carcinogenesis
Abstract

Metastatic castration-resistant prostate cancer (mCRPC) is a highly aggressive disease with few therapeutic options. Hyperactive androgen receptor (AR) signaling plays a key role in CRPC progression. Previously, we identified RAR-related orphan receptor gamma (RORγ) as a novel key driver of AR gene overexpression and increased AR signaling. We report here that several RORγ antagonists/inverse agonists including XY018 and compound 31 were orally effective in potent inhibition of the growth of tumor models including patient-derived xenograft (PDX) tumors. RORγ controls the expression of multiple aggressive-tumor gene programs including those of epithelial-mesenchymal transition (EMT) and invasion. We found that PDZ binding kinase (PBK), a serine/threonine kinase, is a downstream target of RORγ that exerts the cellular effects. Alterations of RORγ expression or function significantly downregulated the mRNA and protein level of PBK. Our further analyses demonstrated that elevated PBK associates with and stabilizes RORγ and AR proteins, thus constituting novel, interlocked feed-forward loops in hyperactive AR and RORγ signaling. Indeed, dual inhibition of RORγ and PBK synergistically inhibited the expression and function of RORγ, AR, and AR-V7, and the growth and survival of CRPC cells. Therefore, our study provided a promising, new strategy for treatment of advanced forms of prostate cancer.

Published
2021

37. Targeting castration-resistant prostate cancer with a novel RORγ antagonist elaiophylin

Author

Zheng, Jianwei, Wang, Junfeng, Wang, Qian, Zou, Hongye, Wang, Hong, Zhang, Zhenhua, Chen, Jianghe, Wang, Qianqian, Wang, Panxia, Zhao, Yueshan, Lu, Jing, Zhang, Xiaolei, Xiang, Songtao, Wang, Haibin, Lei, Jinping, Chen, Hong-Wu, Liu, Peiqing, Liu, Yonghong, Han, Fanghai, and Wang, Junjian

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Prostate Cancer, Genetics, Biotechnology, Aging, Urologic Diseases, Cancer, 5.1 Pharmaceuticals, 2.1 Biological and endogenous factors, Development of treatments and therapeutic interventions, Aetiology, ROR gamma, Castration-resistant prostate cancer, Nuclear receptor, Antagonist, Elaiophylin, RORγ, Pharmacology and pharmaceutical sciences
Abstract

Prostate cancer (PCa) patients who progress to metastatic castration-resistant PCa (mCRPC) mostly have poor outcomes due to the lack of effective therapies. Our recent study established the orphan nuclear receptor RORγ as a novel therapeutic target for CRPC. Here, we reveal that elaiophylin (Elai), an antibiotic from Actinomycete streptomyces, is a novel RORγ antagonist and showed potent antitumor activity against CRPC in vitro and in vivo. We demonstrated that Elai selectively binded to RORγ protein and potently blocked RORγ transcriptional regulation activities. Structure-activity relationship studies showed that Elai occupied the binding pocket with several key interactions. Furthermore, Elai markedly reduced the recruitment of RORγ to its genomic DNA response element (RORE), suppressed the expression of RORγ target genes AR and AR variants, and significantly inhibited PCa cell growth. Importantly, Elai strongly suppressed tumor growth in both cell line based and patient-derived PCa xenograft models. Taken together, these results suggest that Elai is novel therapeutic RORγ inhibitor that can be used as a drug candidate for the treatment of human CRPC.

Published
2020

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