Anti-androgen 2-hydroxyflutamide modulates cadherin, catenin and androgen receptor phosphorylation in androgen-sensitive LNCaP and androgen-independent PC3 prostate cancer cell lines acting via PI3K/Akt and MAPK/ERK1/2 pathways.
This study aimed to investigate rapid effect of anti-androgen 2-hydroxyflutamide (HF) on cadherin/catenin complex and androgen receptor (AR) phosphorylation in prostate cancer cell lines. In addition, a role of PI3K/Akt and MAPK/ERK1/2 pathways in mediating these effects was explored. We have demonstrated that in androgen-sensitive LNCaP cells HF induced rapid increase of E-cadherin phosphorylation at Ser 838/840 (p<0.05) in MAPK/ERK1/2-dependent manner, whereas phosphorylation of β-catenin at Tyr 654 was unchanged. Concomitantly, the reduction of the level of AR phosphorylated at Ser210/213 was found (p<0.01). In androgen-independent PC3 cells HF decreased Tyr 860 N-cadherin and Tyr 645 β-catenin phosphorylation (p<0.01), acting via both MAPK/ERK1/2 and PI3K/Akt pathways. Further, we evidenced that MAPK/ERK1/2 and PI3K/Akt pathways were differentially influenced by HF in LNCaP and PC3 cells. In LNCaP cells, both Akt (p<0.01) and ERK1/2 (p<0.001) phosphorylation were negatively regulated and this effect was mediated by Raf-1 (p<0.05). In contrast, in PC3 cells HF stimulated Akt (p<0.001) and ERK1/2 (p<0.001) activation, but had no effect on the crosstalk between PI3K/Akt and MEK/ERK1/2 pathways at the Raf-1 kinase level. Our findings expand the role of anti-androgen into non-genomic signaling, creating a link between anti-androgen action and phosphorylation of adherens junction proteins in prostate cancer cells.
Department of Endocrinology, Institute of Zoology, Jagiellonian University, Krakow, Poland.
Ewelina
E
Górowska-Wójtowicz
Department of Endocrinology, Institute of Zoology, Jagiellonian University, Krakow, Poland. Electronic address: anna.hejmej@uj.edu.pl.
Anna
A
Hejmej
Department of Endocrinology, Institute of Zoology, Jagiellonian University, Krakow, Poland.
Alicja
A
Kamińska
Department of Endocrinology, Institute of Zoology, Jagiellonian University, Krakow, Poland.
Laura
L
Pardyak
Department of Endocrinology, Institute of Zoology, Jagiellonian University, Krakow, Poland.
Małgorzata
M
Kotula-Balak
Chair of Medical Biochemistry, Jagiellonian University Medical College, Kraków, Poland.
Joanna
J
Dulińska-Litewka
Chair of Medical Biochemistry, Jagiellonian University Medical College, Kraków, Poland.
Piotr
P
Laidler
Department of Endocrinology, Institute of Zoology, Jagiellonian University, Krakow, Poland.
Barbara
B
Bilińska
D000726:Androgen Antagonists / Q000494:pharmacology*; D015703:Antigens, CD / Q000378:metabolism; D015820:Cadherins / Q000378:metabolism; D045744:Cell Line, Tumor; D005485:Flutamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011471:Prostatic Neoplasms / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011944:Receptors, Androgen / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
C410798:AR protein, human; D000726:Androgen Antagonists; D015703:Antigens, CD; C513384:CDH1 protein, human; C050361:CDH2 protein, human; D015820:Cadherins; D011944:Receptors, Androgen; D051176:beta Catenin; C014290:hydroxyflutamide; D005485:Flutamide; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases
Akt; Androgen receptor; Anti-androgen; Cell junctions; ERK1/2; Prostate cancer