Research Papers:
Mechanistic rationale for MCL1 inhibition during androgen deprivation therapy
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Abstract
Frédéric R. Santer1, Holger H. H. Erb1,2, Su Jung Oh1, Florian Handle1, Gertrud E. Feiersinger1, Birgit Luef1, Huajie Bu1, Georg Schäfer1, Christian Ploner3, Martina Egger1, Jayant K. Rane2, Norman J. Maitland2, Helmut Klocker1, Iris E. Eder1,* and Zoran Culig1,*
1 Medical University of Innsbruck, Department of Urology, Division of Experimental Urology, Innsbruck, Austria
2 Yorkshire Cancer Research Unit, University of York, York, United Kingdom
3 Medical University of Innsbruck, Department of Plastic, Reconstructive & Aesthetic Surgery, Innsbruck, Austria
* Joint senior authors
Correspondence to:
Zoran Culig, email:
Keywords: endocrine therapy, cell cycle arrest, cell death, treatment resistance, BCL2 family
Received: December 20, 2014 Accepted: January 13, 2015 Published: January 14, 2015
Abstract
Androgen deprivation therapy induces apoptosis or cell cycle arrest in prostate cancer (PCa) cells. Here we set out to analyze whether MCL1, a known mediator of chemotherapy resistance regulates the cellular response to androgen withdrawal. Analysis of MCL1 protein and mRNA expression in PCa tissue and primary cell culture specimens of luminal and basal origin, respectively, reveals higher expression in cancerous tissue compared to benign origin. Using PCa cellular models in vitro and in vivo we show that MCL1 expression is upregulated in androgen-deprived PCa cells. Regulation of MCL1 through the AR signaling axis is indirectly mediated via a cell cycle-dependent mechanism. Using constructs downregulating or overexpressing MCL1 we demonstrate that expression of MCL1 prevents induction of apoptosis when PCa cells are grown under steroid-deprived conditions. The BH3-mimetic Obatoclax induces apoptosis and decreases MCL1 expression in androgen-sensitive PCa cells, while castration-resistant PCa cells are less sensitive and react with an upregulation of MCL1 expression. Synergistic effects of Obatoclax with androgen receptor inactivation can be observed. Moreover, clonogenicity of primary basal PCa cells is efficiently inhibited by Obatoclax. Altogether, our results suggest that MCL1 is a key molecule deciding over the fate of PCa cells upon inactivation of androgen receptor signaling.
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