Mechanistic rationale for MCL1 inhibition during androgen deprivation therapy.
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.
Medical University of Innsbruck, Department of Urology, Division of Experimental Urology, Innsbruck, Austria.
Frédéric R
FR
Santer
Medical University of Innsbruck, Department of Urology, Division of Experimental Urology, Innsbruck, Austria.|Yorkshire Cancer Research Unit, University of York, York, United Kingdom.
Holger H H
HH
Erb
Medical University of Innsbruck, Department of Urology, Division of Experimental Urology, Innsbruck, Austria.
Su Jung
SJ
Oh
Medical University of Innsbruck, Department of Urology, Division of Experimental Urology, Innsbruck, Austria.
Florian
F
Handle
Medical University of Innsbruck, Department of Urology, Division of Experimental Urology, Innsbruck, Austria.
Gertrud E
GE
Feiersinger
Medical University of Innsbruck, Department of Urology, Division of Experimental Urology, Innsbruck, Austria.
Birgit
B
Luef
Medical University of Innsbruck, Department of Urology, Division of Experimental Urology, Innsbruck, Austria.
Huajie
H
Bu
Medical University of Innsbruck, Department of Urology, Division of Experimental Urology, Innsbruck, Austria.
Georg
G
Schäfer
Medical University of Innsbruck, Department of Plastic, Reconstructive & Aesthetic Surgery, Innsbruck, Austria.
Christian
C
Ploner
Medical University of Innsbruck, Department of Urology, Division of Experimental Urology, Innsbruck, Austria.
Martina
M
Egger
Yorkshire Cancer Research Unit, University of York, York, United Kingdom.
Jayant K
JK
Rane
Yorkshire Cancer Research Unit, University of York, York, United Kingdom.
Norman J
NJ
Maitland
Medical University of Innsbruck, Department of Urology, Division of Experimental Urology, Innsbruck, Austria.
Helmut
H
Klocker
Medical University of Innsbruck, Department of Urology, Division of Experimental Urology, Innsbruck, Austria.
Iris E
IE
Eder
Medical University of Innsbruck, Department of Urology, Division of Experimental Urology, Innsbruck, Austria.
Zoran
Z
Culig
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D006801:Humans; D007211:Indoles; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D011758:Pyrroles / Q000494:pharmacology*; D011897:Random Allocation; D011944:Receptors, Androgen / Q000378:metabolism*; D012307:Risk Factors; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
C410798:AR protein, human; D007211:Indoles; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D011758:Pyrroles; D011944:Receptors, Androgen; C520962:obatoclax
BCL2 family; cell cycle arrest; cell death; endocrine therapy; treatment resistance