title: PIAS1 is a crucial factor for prostate cancer cell survival and a valid target in docetaxel resistant cells.
abstract: Occurrence of an inherent or acquired resistance to the chemotherapeutic drug docetaxel is a major burden for patients suffering from different kinds of malignancies, including castration resistant prostate cancer (PCa). In the present study we address the question whether PIAS1 targeting can be used to establish a basis for improved PCa treatment. The expression status and functional relevance of PIAS1 was evaluated in primary tumors, in metastatic lesions, in tissue of patients after docetaxel chemotherapy, and in docetaxel resistant cells. Patient data were complemented by functional studies on PIAS1 knockdown in vitro as well as in chicken chorioallantoic membrane and mouse xenograft in vivo models. PIAS1 was found to be overexpressed in local and metastatic PCa and its expression was further elevated in tumors after docetaxel treatment as well as in docetaxel resistant cells. Furthermore, PIAS1 knockdown experiments revealed an increased expression of tumor suppressor p21 and declined expression of anti-apoptotic protein Mcl1, which caused diminished cell proliferation and tumor growth in vitro and in vivo. In summary, the presented data indicate that PIAS1 is crucial for parental and docetaxel resistant PCa cell survival and is therefore a promising new target for treatment of primary, metastatic, and chemotherapy resistant PCa.
authors.affiliation: Experimental Urology, Department of Urology, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Martin
authors.initials: M
authors.lastname: Puhr
authors.affiliation: Experimental Urology, Department of Urology, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Julia
authors.initials: J
authors.lastname: Hoefer
authors.affiliation: Department of Internal Medicine IV (Nephrology and Hypertension), Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Hannes
authors.initials: H
authors.lastname: Neuwirt
authors.affiliation: Experimental Urology, Department of Urology, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Iris E
authors.initials: IE
authors.lastname: Eder
authors.affiliation: Oncotyrol Laboratory for Tumor Biology and Angiogenesis, Innsbruck, Austria.
authors.forename: Johann
authors.initials: J
authors.lastname: Kern
authors.affiliation: Experimental Urology, Department of Urology, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Georg
authors.initials: G
authors.lastname: Schäfer
authors.affiliation: Division of Molecular Pathophysiology, Innsbruck Biocenter, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Stephan
authors.initials: S
authors.lastname: Geley
authors.affiliation: Experimental Urology, Department of Urology, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Isabel
authors.initials: I
authors.lastname: Heidegger
authors.affiliation: Experimental Urology, Department of Urology, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Helmut
authors.initials: H
authors.lastname: Klocker
authors.affiliation: Experimental Urology, Department of Urology, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Zoran
authors.initials: Z
authors.lastname: Culig
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000502:physiology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002470:Cell Survival; D000077143:Docetaxel; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D005455:Fluorescent Antibody Technique; D064593:Heterografts; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D011471:Prostatic Neoplasms / Q000378:metabolism*; D050828:Protein Inhibitors of Activated STAT / Q000378:metabolism*; D034741:RNA, Small Interfering; D020133:Reverse Transcriptase Polymerase Chain Reaction; D025841:Small Ubiquitin-Related Modifier Proteins / Q000378:metabolism*; D043823:Taxoids / Q000494:pharmacology*; D046888:Tissue Array Analysis; D014162:Transfection
chemical_list: D000970:Antineoplastic Agents; C106529:PIAS1 protein, human; D050828:Protein Inhibitors of Activated STAT; D034741:RNA, Small Interfering; D025841:Small Ubiquitin-Related Modifier Proteins; D043823:Taxoids; D000077143:Docetaxel