The role of androgen in prostate cancer cell invasion
Author: Chuan, Yin-Choy
Date: 2008-06-12
Location: Föreläsningssalen, CMM L8:00, Karolinska Universitetssjukhuset, Solna
Time: 13.00
Department: Institutionen för molekylär medicin och kirurgi / Department of Molecular Medicine and Surgery
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thesis.pdf (809.2Kb)
Abstract
Prostate cancer (PCa) is the most commonly diagnosed cancer in men in
developed countries. Androgen deprivation therapy (ADT) is the mainstay
treatment for patient diagnosed with PCa. However, the cancer will
eventually relapse with metastatic cancer and become resistant to the
treatment. Since mortality in PCa is due to our inability to manage
metastatic cancer, there is a great need for a better understanding of
the cancer progression to develop novel therapeutic principles. As
reflected by the therapeutic effects of (ADT) for PCa, it has become
clear that intact androgen receptor signaling is necessary for the
development of the disease. Previous works in our group have focused on
studies of androgen regulated genes in a systematic and high-throughput
manner using microarray technology. In those studies, several
androgen-regulated genes were identified, some of which could be
important in the regulation of PCa cell invasion.
The aim of this thesis was to characterize a set of androgen-regulated genes in PCa and investigate the role of androgen on PCa cell invasion and the mode of actions of those selected genes in the invasion process.
In this thesis, we demonstrate that androgen stimulation of the androgen sensitive PCa cell line, LNCaP-FGC up-regulate those selected genes at both mRNA and protein levels. For the first time, we also demonstrated that androgen induces the invasiveness of LNCaP-FGC through matrigel. This process was mediated by Ezrin, one of our selected genes. Androgen treatment phosphorylates ezrin in Thr-567 and Tyr-353 in a sequential manner and can also induce ezrin gene expression. The phosphorylation event was mediated by protein kinase C alpha and Src tyrosine kinase, respectively. Androgen furthermore induces the translocation of both protein kinase C alpha and ezrin to the cell membrane and their association. Inhibition of ezrin using short interference RNA or the overexpression of T567A and Y353F-ezrin mutants significantly reduces androgen-induced Matrigel invasion but does not affect cell proliferation or cell adhesion.
We also demonstrate that androgens also increase gene expression of ezrin in LNCaP-FGC cell, through a mechanism involving the transcription factor c-Myc. Our finding that c-Myc binds to an E-Box in Ezrin promoter region leads us to suggest that androgen induction of ezrin is indirect and mediated by c-Myc. In addition, androgen treatment prolonged the half-life of c-Myc protein in LNCaP-FGC. We propose that this effect is achieved through changes in Ezrin phosphorylation, which leads to activation of downstream Akt and downregulation of GSK-3β signaling resulting in the inhibition of the degradation of c-Myc protein. Ezrin protein expression and cell invasion in two other androgen insensitive cell lines, LNCaP-R and PC3 are also depend on c-Myc.
In conclusion, we have shown that androgen can induce PCa cell invasion that mediated through two distinct proteins c-Myc and ezrin. Ezrin also acts as a key modulator of c-Myc induced tumorigenesis in PCa cells
The aim of this thesis was to characterize a set of androgen-regulated genes in PCa and investigate the role of androgen on PCa cell invasion and the mode of actions of those selected genes in the invasion process.
In this thesis, we demonstrate that androgen stimulation of the androgen sensitive PCa cell line, LNCaP-FGC up-regulate those selected genes at both mRNA and protein levels. For the first time, we also demonstrated that androgen induces the invasiveness of LNCaP-FGC through matrigel. This process was mediated by Ezrin, one of our selected genes. Androgen treatment phosphorylates ezrin in Thr-567 and Tyr-353 in a sequential manner and can also induce ezrin gene expression. The phosphorylation event was mediated by protein kinase C alpha and Src tyrosine kinase, respectively. Androgen furthermore induces the translocation of both protein kinase C alpha and ezrin to the cell membrane and their association. Inhibition of ezrin using short interference RNA or the overexpression of T567A and Y353F-ezrin mutants significantly reduces androgen-induced Matrigel invasion but does not affect cell proliferation or cell adhesion.
We also demonstrate that androgens also increase gene expression of ezrin in LNCaP-FGC cell, through a mechanism involving the transcription factor c-Myc. Our finding that c-Myc binds to an E-Box in Ezrin promoter region leads us to suggest that androgen induction of ezrin is indirect and mediated by c-Myc. In addition, androgen treatment prolonged the half-life of c-Myc protein in LNCaP-FGC. We propose that this effect is achieved through changes in Ezrin phosphorylation, which leads to activation of downstream Akt and downregulation of GSK-3β signaling resulting in the inhibition of the degradation of c-Myc protein. Ezrin protein expression and cell invasion in two other androgen insensitive cell lines, LNCaP-R and PC3 are also depend on c-Myc.
In conclusion, we have shown that androgen can induce PCa cell invasion that mediated through two distinct proteins c-Myc and ezrin. Ezrin also acts as a key modulator of c-Myc induced tumorigenesis in PCa cells
List of papers:
I. Pang ST, Flores-Morales A, Skoog L, Chuan YC, Nordstedt G, Pousette A (2004). "Regulation of matrix metalloproteinase 13 expression by androgen in prostate cancer." Oncol Rep 11(6): 1187-92
Pubmed
II. Chuan Y, Pang ST, Bergh A, Norstedt G, Pousette A (2005). "Androgens induce CD-9 in human prostate tissue." Int J Androl 28(5): 291-6
Pubmed
III. Chuan YC, Pang ST, Cedazo-Minguez A, Norstedt G, Pousette A, Flores-Morales A (2006). "Androgen induction of prostate cancer cell invasion is mediated by ezrin." J Biol Chem 281(40): 29938-48. Epub 2006 Jul 26
Pubmed
IV. Chuan YC, Iglesias-Gato D, Fernandez-Perez L, Norstedt G, Pousette Å, Flores-Morales A (2008). "Ezrin mediates c-Myc actions in prostate cancer cells invasion." (Submitted)
I. Pang ST, Flores-Morales A, Skoog L, Chuan YC, Nordstedt G, Pousette A (2004). "Regulation of matrix metalloproteinase 13 expression by androgen in prostate cancer." Oncol Rep 11(6): 1187-92
Pubmed
II. Chuan Y, Pang ST, Bergh A, Norstedt G, Pousette A (2005). "Androgens induce CD-9 in human prostate tissue." Int J Androl 28(5): 291-6
Pubmed
III. Chuan YC, Pang ST, Cedazo-Minguez A, Norstedt G, Pousette A, Flores-Morales A (2006). "Androgen induction of prostate cancer cell invasion is mediated by ezrin." J Biol Chem 281(40): 29938-48. Epub 2006 Jul 26
Pubmed
IV. Chuan YC, Iglesias-Gato D, Fernandez-Perez L, Norstedt G, Pousette Å, Flores-Morales A (2008). "Ezrin mediates c-Myc actions in prostate cancer cells invasion." (Submitted)
Issue date: 2008-05-22
Rights:
Publication year: 2008
ISBN: 978-91-7409-034-5
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