PMID- 23798432
OWN - NLM
STAT- MEDLINE
DCOM- 20131018
LR  - 20220331
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 110
IP  - 28
DP  - 2013 Jul 9
TI  - Molecular circuit involving KLK4 integrates androgen and mTOR signaling in 
      prostate cancer.
PG  - E2572-81
LID - 10.1073/pnas.1304318110 [doi]
AB  - The androgen receptor (AR) and the phosphoinositide 3-kinase (PI3K)/protein 
      kinase B/mammalian target of rapamycin (mTOR) signaling are two of the major 
      proliferative pathways in a number of tissues and are the main therapeutic 
      targets in various disorders, including prostate cancer (PCa). Previous work has 
      shown that there is reciprocal feedback regulation of PI3K and AR signaling in 
      PCa, suggesting that cotargeting both pathways may enhance therapeutic efficacy. 
      Here we show that proteins encoded by two androgen-regulated genes, kallikrein 
      related peptidase 4 (KLK4) and promyelocytic leukemia zinc finger (PLZF), 
      integrate optimal functioning of AR and mTOR signaling in PCa cells. KLK4 
      interacts with PLZF and decreases its stability. PLZF in turn interacts with AR 
      and inhibits its function as a transcription factor. PLZF also activates 
      expression of regulated in development and DNA damage responses 1, an inhibitor 
      of mTORC1. Thus, a unique molecular switch is generated that regulates both AR 
      and PI3K signaling. Consistently, KLK4 knockdown results in a significant decline 
      in PCa cell proliferation in vitro and in vivo, decreases anchorage-independent 
      growth, induces apoptosis, and dramatically sensitizes PCa cells to 
      apoptosis-inducing agents. Furthermore, in vivo nanoliposomal KLK4 siRNA delivery 
      in mice bearing PCa tumors results in profound remission. These results 
      demonstrate that the activities of AR and mTOR pathways are maintained by KLK4, 
      which may thus be a viable target for therapy.
FAU - Jin, Yang
AU  - Jin Y
AD  - Department of Biosciences, University of Oslo, 0316 Oslo, Norway.
FAU - Qu, Su
AU  - Qu S
FAU - Tesikova, Martina
AU  - Tesikova M
FAU - Wang, Ling
AU  - Wang L
FAU - Kristian, Alexandr
AU  - Kristian A
FAU - Maelandsmo, Gunhild M
AU  - Maelandsmo GM
FAU - Kong, Haiying
AU  - Kong H
FAU - Zhang, Tianzhou
AU  - Zhang T
FAU - Jeronimo, Carmen
AU  - Jeronimo C
FAU - Teixeira, Manuel R
AU  - Teixeira MR
FAU - Yuca, Erkan
AU  - Yuca E
FAU - Tekedereli, Ibrahim
AU  - Tekedereli I
FAU - Gorgulu, Kivanc
AU  - Gorgulu K
FAU - Alpay, Neslihan
AU  - Alpay N
FAU - Sood, Anil K
AU  - Sood AK
FAU - Lopez-Berestein, Gabriel
AU  - Lopez-Berestein G
FAU - Danielsen, Havard E
AU  - Danielsen HE
FAU - Ozpolat, Bulent
AU  - Ozpolat B
FAU - Saatcioglu, Fahri
AU  - Saatcioglu F
LA  - eng
GR  - P30 CA016672/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20130624
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (Androgens)
RN  - 0 (Receptors, Androgen)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (Ribosomal Protein S6 Kinases)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 3.4.21.- (Kallikreins)
RN  - EC 3.4.21.- (kallikrein 4)
SB  - IM
MH  - Androgens/*metabolism
MH  - Cell Death
MH  - Cell Division
MH  - Enzyme Activation
MH  - G1 Phase
MH  - Gene Knockdown Techniques
MH  - Humans
MH  - Kallikreins/genetics/*physiology
MH  - Male
MH  - Prostatic Neoplasms/*metabolism/pathology
MH  - Receptors, Androgen/metabolism
MH  - Ribosomal Protein S6 Kinases/metabolism
MH  - *Signal Transduction
MH  - TOR Serine-Threonine Kinases/*metabolism
PMC - PMC3710885
COIS- The authors declare no conflict of interest.
EDAT- 2013/06/27 06:00
MHDA- 2013/10/19 06:00
PMCR- 2014/01/09
CRDT- 2013/06/27 06:00
PHST- 2013/06/27 06:00 [entrez]
PHST- 2013/06/27 06:00 [pubmed]
PHST- 2013/10/19 06:00 [medline]
PHST- 2014/01/09 00:00 [pmc-release]
AID - 1304318110 [pii]
AID - 201304318 [pii]
AID - 10.1073/pnas.1304318110 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2013 Jul 9;110(28):E2572-81. doi: 
      10.1073/pnas.1304318110. Epub 2013 Jun 24.