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

Zheng, Jie; Wang, Junfeng; Wang, Qian; Zou, Hongye; Wang, Hong; Zhang, Zhenhua; Chen, Jianghe; Wang, Qianqian; Wang, Panxia; Zhao, Yueshan; Lu, Jing; Zhang, Xiaolei; Xiang, Shulin; Wang, Haibin; Lei, Jinping; Chen, Hong Wu; Liu, Yonghong; Han, Fanghai; Wang, Junjian

doi:10.1016/j.apsb.2020.07.001

Cited by 24 publications

(29 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Recent studies demonstrate that certain oxysterols and intermediates of cholesterol biosynthesis can serve as endogenous RORγ activating ligands/agonists [ 19 ]. We previously reported a series of RORγ antagonists/inverse agonists with different scaffolds [ 18 , 20 , 21 , 22 , 23 ]. Compounds with biphenyl-4-yl-amines and related scaffolds displayed potent anti-tumor activities in cell culture and in tumor models [ 18 , 22 , 23 , 24 , 25 ].…”

Section: Introductionmentioning

confidence: 99%

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

Zhang

Huang

Wang

et al. 2021

Cancers

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Introductionmentioning

confidence: 99%

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

Zhang

Huang

Wang

et al. 2021

Cancers

Self Cite

View full text Add to dashboard Cite

show abstract

“…For instance, Elaiohylin exerted prominent antitumor e cacy as an autophagy inhibitor in ovarian cancer 7 and multiple myeloma with mutant TP53, which was also involved ER stress-associated apoptosis 8 . Besides, Elaiophylin could inhibit tumor progression and suppressed tumor growth in xenograft of metastatic castration-resistant prostate cancer (mCRPC), which was targeting the orphan nuclear receptor RORγ 13 . On the other hand, Elaiophylin has also been proved to inhibit angiogenesis in cancers as well as proliferation, migration and invasion accompanied by it.…”

Section: Discussionmentioning

confidence: 99%

Elaiophylin Targets EIF4B to Regulate the Proliferation, Invasion, and Apoptosis of Esophageal Squamous Cell Carcinoma via the PI3K/AKT Signaling Pathway

Gao

Chen

2021

Preprint

View full text Add to dashboard Cite

BackgroundEsophageal cancer remains a dominating cause of cancer-associated death and has shown a sharp increase of more than 6-fold increase rates all over the world. It is divided into two main pathological types: esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC). Most of the patients are diagnosed at the advanced stage with distant metastasis and poor prognosis. Thus, it is urgent for us to identify new more effective drugs to improve the prognosis of patients with esophageal cancer. Elaiophylin is a novel autophagy inhibitor at the late stage, which is a C2 symmetric macrolides separated from Streptomyces Niger. It was proved to have anti-tumor ability of various of cancers, yet little is known whether it could inhibit the progression of esophageal squamous cancer. The study is aimed to explore the effect of Elaiophylin on ESCC. MethodsThe protein expression level was detected by western blot assay. The viability of ESCC cells was detected by CCK8 assay. The proliferation rate was measured by ki67 immunofluorescent staining. The migratory ability of ESCC cells was identified by transwell assay. The apoptosis rate of ESCC cells was explored by Annexin V/PI analysis. And the genes might be regulated by Elaiophylin was analyzed by RNA-seq assay and verified by RT-qPCR assay. The experiments in vivo were conducted by subcutaneous into tumor in BALB/C-Nu mice. ResultsIn the study, we firstly found that the Elaiophylin was a novel autophagy inhibitor in ESCC cells which is consistent with the previous studies. In addition, Elaiophylin can inhibit the proliferation and migration of ESCCs, and accelerate its apoptosis. And the activity of PI3K/AKT pathway was inhibited by Elaiophylin, the mRNA and protein expression level of EIF4B was both downregulated by Elaiophylin. Mechanistically, silencing of EIF4B could inhibit the proliferation and migration of ESCC cells and promoted apoptosis, which could be rescued by EIF4B-OE. Moreover, EIF4B overexpression suppressed the apoptosis, while increased the proliferation and migration of ESCC cells which resulted from Elaiophylin. Finally, Elaiophylin could inhibit the proliferation of esophageal cancer in vivo compared to the control group. ConclusionsTogether, our results indicated that Elaiophylin is a novel autophagy inhibitor governing growth and migratory ability of ESCC cells through PI3K/AKT signaling pathway and inhibit the proliferation of esophageal tumor in vivo. simultaneously, and identified EIF4B as a target of Elaiophylin, which might provide a new therapeutic strategy for esophageal squamous cell carcinoma.

show abstract

“…Western blotting was performed with the indicated primary antibodies as our previous reports [ 36 ]. For siRNA transfection, siRNAs were obtained from Sangon Biotech (shanghai) Co., Ltd.…”

Section: Methodsmentioning

confidence: 99%

Targeting autophagy peptidase ATG4B with a novel natural product inhibitor Azalomycin F4a for advanced gastric cancer

Yang

Zhang

et al. 2022

Cell Death Dis

Self Cite

View full text Add to dashboard Cite

Advanced gastric cancer (GCa) remains highly lethal due to the lack of effective therapies. Identifying promising therapeutic targets and developing effective treatment against GCa are urgently needed. Through mRNA and protein analysis of GCa clinical tumor samples, we found that autophagy-related gene 4B (ATG4B) was overexpressed in GCa tumors and that its high expression was associated with patients’ poor prognosis. Knockdown of ATG4B significantly inhibited GCa cell survival and tumor growth. To further probe the role of ATG4B in GCa by pharmacological means, we screened an in-house marine natural compound library against ATG4B and identified Azalomycin F4a (Am-F4a) as a novel and potent ATG4B inhibitor. Am-F4a directly bound to ATG4B with high affinity and effectively suppressed GCa cell autophagy via inhibition of ATG4B both in vitro and in vivo. Moreover, Am-F4a or ATG4B knockdown significantly suppressed tumor growth as well as GCa cell migration and invasion. Am-F4a effectively blocked the metastatic progression of primary GCa and sensitized tumors to chemotherapy. Taken together, our findings indicate that ATG4B is a potential therapeutic target against GCa and the natural product Am-F4a is a novel ATG4B inhibitor that can be further developed for the treatment of GCa.

show abstract

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

Cited by 24 publications

References 34 publications

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

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

Elaiophylin Targets EIF4B to Regulate the Proliferation, Invasion, and Apoptosis of Esophageal Squamous Cell Carcinoma via the PI3K/AKT Signaling Pathway

Targeting autophagy peptidase ATG4B with a novel natural product inhibitor Azalomycin F4a for advanced gastric cancer

Contact Info

Product

Resources

About