Oncotarget

Research Papers:

PIAS1 is a crucial factor for prostate cancer cell survival and a valid target in docetaxel resistant cells

Martin Puhr _, Julia Hoefer, Hannes Neuwirt, Iris E. Eder, Johann Kern, Georg Schäfer, Stephan Geley, Isabel Heidegger, Helmut Klocker and Zoran Culig

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Oncotarget. 2014; 5:12043-12056. https://doi.org/10.18632/oncotarget.2658

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Abstract

Martin Puhr1, Julia Hoefer1, Hannes Neuwirt2, Iris E. Eder1, Johann Kern3, Georg Schäfer1, Stephan Geley4, Isabel Heidegger1, Helmut Klocker1, Zoran Culig1

1Experimental Urology, Department of Urology, Medical University of Innsbruck, Innsbruck, Austria

2Department of Internal Medicine IV (Nephrology and Hypertension), Medical University of Innsbruck, Innsbruck, Austria

3Oncotyrol Laboratory for Tumor Biology and Angiogenesis, Innsbruck, Austria

4Division of Molecular Pathophysiology, Innsbruck Biocenter, Medical University of Innsbruck, Innsbruck, Austria

Correspondence to:

Martin Puhr, e-mail: [email protected]

Zoran Culig, e-mail: [email protected]

Keywords: prostate cancer, PIAS1, docetaxel, chemotherapy resistance, apoptosis

Received: August 06, 2014     Accepted: October 27, 2014     Published: November 17, 2014

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.


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