title: The role of TXNDC5 in castration-resistant prostate cancer-involvement of androgen receptor signaling pathway.
abstract: Castration-resistant prostate cancer (CRPC) continues to be a major clinical problem and the mechanisms behind it remain unclear. Thioredoxin domain-containing protein 5 (TXNDC5) is involved in protein folding and chaperone activity, and its overexpression has been reported in multiple malignancies. In the current study, we demonstrated that TXNDC5 is up-regulated following long-term androgen-deprivation treatment (ADT) and is highly overexpressed in CRPC tumors compared with hormone-naive prostate cancer (PCa) cases. Functionally, in vitro and in vivo studies demonstrated that TXNDC5 overexpression promotes the growth of both androgen-dependent and castration-resistant PCa xenografts. Mechanistically, TXNDC5 directly interacts with the AR protein to increase its stability and thus enhances its transcriptional activity. TXDNC5-mediated CRPC growth can be fully abolished by AR inhibition, suggesting TXDNC5 up-regulation as an escape pathway for aberrant AR re-activation and CRPC growth in the milieu of low androgen. Indeed, we found that TXNDC5 is increased by ADT-induced hypoxia through HIF-1α in an miR-200b-dependent manner. Overall, we defined an important role of TXNDC5 in CRPC and further investigations are needed to screen TXNDC5 antagonists as a novel therapeutic approaches to treat PCa patients with CRPC.
authors.affiliation: Department of Pathology, Shandong University Medical School, Jinan, China.|Research Center for Medicinal Biotechnology, Key Laboratory for Rare & Uncommon Diseases of Shandong Province, Shandong Academy of Medicinal Sciences, Jinan, China.
authors.forename: L
authors.initials: L
authors.lastname: Wang
authors.affiliation: Institute of Basic Medicine, Shandong Academy of Medical Sciences, Jinan, China.
authors.forename: G
authors.initials: G
authors.lastname: Song
authors.affiliation: Medical Research Center of Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, China.
authors.forename: X
authors.initials: X
authors.lastname: Chang
authors.affiliation: Department of Pathology, Shandong University Medical School, Jinan, China.
authors.forename: W
authors.initials: W
authors.lastname: Tan
authors.affiliation: Research Center for Medicinal Biotechnology, Key Laboratory for Rare & Uncommon Diseases of Shandong Province, Shandong Academy of Medicinal Sciences, Jinan, China.
authors.forename: J
authors.initials: J
authors.lastname: Pan
authors.affiliation: Shandong institute of medicine and health informations, Jinan, China.
authors.forename: X
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Department of Pathology, Shandong University Medical School, Jinan, China.|Department of Pathology, Shandong University Qilu hospital, Jinan, China.
authors.forename: Z
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Pathology, Shandong University Medical School, Jinan, China.
authors.forename: M
authors.initials: M
authors.lastname: Qi
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: J
authors.initials: J
authors.lastname: Yu
authors.affiliation: Department of Pathology, Shandong University Medical School, Jinan, China.|Department of Pathology, Shandong University Qilu hospital, Jinan, China.
authors.forename: B
authors.initials: B
authors.lastname: Han
mesh_terms: D000728:Androgens / Q000378:metabolism; D000818:Animals; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000235:genetics; D064129:Prostatic Neoplasms, Castration-Resistant / Q000235:genetics* / Q000473:pathology; D019704:Protein Disulfide-Isomerases / Q000096:biosynthesis* / Q000235:genetics; D011944:Receptors, Androgen / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D000728:Androgens; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C533896:MIRN200 microRNA, human; D035683:MicroRNAs; D011944:Receptors, Androgen; D019704:Protein Disulfide-Isomerases; C480743:TXNDC5 protein, human