title: Phosphodiesterase 5/protein kinase G signal governs stemness of prostate cancer stem cells through Hippo pathway.
abstract: Cancer stem cells (CSC) are critical for initiation, metastasis, and relapse of cancers, however, the underlying mechanism governing stemness of CSC remains unknown. Herein, we have investigated the roles of phosphodiesterase 5 (PDE5) in stemness of prostate cancer cells. Both PDE5 and WW domain-containing transcription regulator protein-1 (TAZ), a core effector of Hippo pathway, are highly expressed in the PC3-derived cancer stem cells (PCSC). Either TAZ knockdown or inhibition of PDE5 activity attenuated colony formation, altered expression patterns of stem cell markers, and enhanced cisplatin cytotoxicity, resulting in attenuation of stemness in PCSC. In addition, inhibition of PDE5 activity by its specific inhibitors activates cGMP-dependent protein kinase G (PKG), which in turn induces MST/LATS kinases, resulting in cytosolic degradation of TAZ and activation of Hippo pathway. Accordingly, knockdown of TAZ almost completely abolished PDE5 inhibitor-induced attenuation in stemness in cultured PCSC, whereas knockdown of TAZ not only abolished PDE5 inhibitor-induced attenuation in stemness but also facilitated PDE5 inhibitor-induced trans-differentiation in PCSC xenografts. Together, the present study has uncovered that PDE/cGMP/PKG signal targets to Hippo/TAZ pathway in maintaining stemness of PCSC, and suggested that PDE5 inhibitors in combination with chemotherapeutic agents could effectively prevent initiation, metastasis, and relapse of prostate cancer.
authors.affiliation: Department of Pharmacology, School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Naihua
authors.initials: N
authors.lastname: Liu
authors.affiliation: Department of Pharmacology, School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Liu
authors.initials: L
authors.lastname: Mei
authors.affiliation: Department of Pharmacology, School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Xueying
authors.initials: X
authors.lastname: Fan
authors.affiliation: Department of Pharmacology, School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Tang
authors.affiliation: Department of Pharmacology, School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Xing
authors.initials: X
authors.lastname: Ji
authors.affiliation: Department of Pharmacology, School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Xinhua
authors.initials: X
authors.lastname: Hu
authors.affiliation: Department of Pharmacology, School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Shi
authors.affiliation: Shaoxing People's Hospital of Zhejiang University, Shaoxing, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Qian
authors.affiliation: Department of Pharmacology, School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Musaddique
authors.initials: M
authors.lastname: Hussain
authors.affiliation: The First Affiliated Hospital of Zhejiang University, Hangzhou, China.
authors.forename: Junsong
authors.initials: J
authors.lastname: Wu
authors.affiliation: The First Affiliated Hospital of Zhejiang University, Hangzhou, China.
authors.forename: Chaojun
authors.initials: C
authors.lastname: Wang
authors.affiliation: The First Affiliated Hospital of Jinan University, Guangzhou, China.
authors.forename: Shaoqiang
authors.initials: S
authors.lastname: Lin
authors.affiliation: Department of Pharmacology, School of Medicine, Zhejiang University, Hangzhou, China; Program of Molecular and Cellular Biology, School of Medicine, Zhejiang University, Hangzhou, China. Electronic address: xiwu@zju.edu.cn.
authors.forename: Ximei
authors.initials: X
authors.lastname: Wu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D014408:Biomarkers, Tumor / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D054338:Cell Transdifferentiation; D002945:Cisplatin / Q000494:pharmacology; D006152:Cyclic GMP / Q000378:metabolism; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism*; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5 / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D000090683:Hippo Signaling Pathway; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D010641:Phenotype; D058986:Phosphodiesterase 5 Inhibitors / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D034622:RNA Interference; D015398:Signal Transduction; D013997:Time Factors; D015534:Trans-Activators; D014157:Transcription Factors; D000091364:Transcriptional Coactivator with PDZ-Binding Motif Proteins; D014162:Transfection; D047368:Tumor Burden; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D047908:Intracellular Signaling Peptides and Proteins; D058986:Phosphodiesterase 5 Inhibitors; D015534:Trans-Activators; D014157:Transcription Factors; D000091364:Transcriptional Coactivator with PDZ-Binding Motif Proteins; C551991:WWTR1 protein, human; D017346:Protein Serine-Threonine Kinases; D017869:Cyclic GMP-Dependent Protein Kinases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D006152:Cyclic GMP; D002945:Cisplatin
keywords: Cancer stem cells; Hippo pathway; PDE5; Stemness; TAZ