PMID- 16421604
OWN - NLM
STAT- MEDLINE
DCOM- 20060302
LR  - 20161124
IS  - 0950-9232 (Print)
IS  - 0950-9232 (Linking)
VI  - 25
IP  - 3
DP  - 2006 Jan 19
TI  - PTEN and GSK3beta: key regulators of progression to androgen-independent prostate 
      cancer.
PG  - 329-37
AB  - Prostate cancer (PrCa) is characterized by progression from an androgen-dependent 
      phenotype to one that is inevitably androgen independent (AI) and lethal. Recent 
      evidence strongly suggests that the phosphatidylinositol-3-kinase/Akt (PI3K/Akt) 
      and androgen receptor (AR) signalling pathways provide prostatic epithelium with 
      the necessary signalling events to escape the apoptotic response associated with 
      androgen withdrawal therapy. Silencing of phosphatase and tensin homologue 
      deleted on chromosome 10 (PTEN) and glycogen synthase kinase beta (GSK3beta) are 
      frequently associated with advanced PrCa systems and likely serve critical roles 
      in promoting AR and PI3K/Akt gain-of-function. That PTEN negatively regulates AR 
      and is sufficient to promote metastatic PrCa in murine models strongly implies 
      its role as a gatekeeper of progressive PrCa. In human PrCa, PTEN loss is 
      correlated with substantial increases in Akt(Ser473) and integrin-linked kinase 
      expression, both of which promote Ser(9) phospho-inhibition of GSK3beta and 
      inactivation of apoptotic factors. Sufficient evidence also suggests that 
      GSK3beta is not only a critical regulator of proproliferative signalling but also 
      a promiscuous one as PI3K/Akt pools of GSK3beta are, at least in part, 
      functionally interchangeable with those of the Wnt/beta-catenin pathway. Thus, 
      GSK3beta may serve not only as a mediator of PI3K/Akt activation but may also 
      regulate the potent transactivation and proproliferative effects that Wnt3a and 
      beta-catenin confer upon AR. These data suggest that prostate-specific activation 
      of GSK3beta may serve as a viable pharmacological option. Thus, in this review, 
      we emphasize that temporal changes in GSK3beta and PTEN expression during 
      progression to AI PrCa are important factors when considering the potential for 
      therapies targeting the oncogenic contributions of PI3K/Akt and AR signalling 
      pathways.
FAU - Mulholland, D J
AU  - Mulholland DJ
AD  - Department of Molecular and Medical Pharmacology, UCLA School of Medicine, Los 
      Angeles, CA 90095, USA. dmulholland@mednet.ucla.edu
FAU - Dedhar, S
AU  - Dedhar S
FAU - Wu, H
AU  - Wu H
FAU - Nelson, C C
AU  - Nelson CC
LA  - eng
PT  - Journal Article
PT  - Review
PL  - England
TA  - Oncogene
JT  - Oncogene
JID - 8711562
RN  - 0 (Androgens)
RN  - EC 2.7.11.1 (GSK3B protein, human)
RN  - EC 2.7.11.1 (Glycogen Synthase Kinase 3 beta)
RN  - EC 2.7.11.26 (Glycogen Synthase Kinase 3)
RN  - EC 3.1.3.67 (PTEN Phosphohydrolase)
RN  - EC 3.1.3.67 (PTEN protein, human)
SB  - IM
MH  - Androgens/*physiology
MH  - Disease Progression
MH  - Glycogen Synthase Kinase 3/*physiology
MH  - Glycogen Synthase Kinase 3 beta
MH  - Humans
MH  - Male
MH  - PTEN Phosphohydrolase/*physiology
MH  - Prostatic Neoplasms/*physiopathology
RF  - 118
EDAT- 2006/01/20 09:00
MHDA- 2006/03/03 09:00
CRDT- 2006/01/20 09:00
PHST- 2006/01/20 09:00 [pubmed]
PHST- 2006/03/03 09:00 [medline]
PHST- 2006/01/20 09:00 [entrez]
AID - 1209020 [pii]
AID - 10.1038/sj.onc.1209020 [doi]
PST - ppublish
SO  - Oncogene. 2006 Jan 19;25(3):329-37. doi: 10.1038/sj.onc.1209020.