PMID- 22911740
OWN - NLM
STAT- MEDLINE
DCOM- 20130419
LR  - 20211021
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 7
IP  - 7
DP  - 2012
TI  - Inhibition of uterine sarcoma cell growth through suppression of endogenous 
      tyrosine kinase B signaling.
PG  - e41049
LID - 10.1371/journal.pone.0041049 [doi]
LID - e41049
AB  - Uterine leiomyosarcoma is an aggressive tumor typically found at advanced stages 
      due to difficulties with early diagnosis. Because uterine leiomyosarcoma is 
      resistant to conventional radiation and chemotherapy, the development of more 
      potent medical therapeutics is anticipated. Using quantitative real-time RT-PCR 
      and immunostaining, we found the expression of brain-derived neurotrophic factor 
      (BDNF) and neurotropin-4/5, together with their receptor, tyrosine kinase B 
      (TrkB), in different uterine sarcoma cell lines and primary tumor samples from 
      uterine leiomyosarcoma patients. We noted that levels of BDNF were more abundant 
      than those of neurotropin-4/5. Moreover, the expression of TrkB and its ligands 
      was elevated in a multidrug-resistant cell line and samples obtained from 
      patients with leiomyosarcoma. In cultured uterine sarcoma cells, inhibition of 
      endogenous TrkB signaling by treatment with either the soluble TrkB ectodomain or 
      the Trk receptor inhibitor, K252a, suppressed cell proliferation and increased 
      apoptosis based on cell viability and proliferation, in situ terminal 
      deoxynucleotidyl transferase-mediated 2'-deoxyuridine 5'-triphosphate nick 
      end-labeling and caspase-3/7 assays, whereas an inactive plasma membrane 
      nonpermeable K252b was ineffective. Correspondingly, treatment with exogenous 
      BDNF increased cell proliferation. In in vivo studies in athymic nude mice 
      bearing multidrug-resistant uterine sarcoma cell tumors, we demonstrate 
      suppression of tumor growth by treatment with K252a, but not K252b, as reflected 
      by decreased cell proliferation and increased levels of apoptosis and caspase-3/7 
      activities without obvious side effects. Our findings indicated that endogenous 
      signaling of the TrkB pathway contributed to uterine sarcoma cell growth, and 
      inhibition of TrkB signaling in these tumors could provide a novel medical 
      therapy for patients with uterine sarcomas.
FAU - Makino, Kenichi
AU  - Makino K
AD  - Department of Obstetrics and Gynecology, Akita University School of Medicine, 
      Akita, Japan.
FAU - Kawamura, Kazuhiro
AU  - Kawamura K
FAU - Sato, Wataru
AU  - Sato W
FAU - Kawamura, Nanami
AU  - Kawamura N
FAU - Fujimoto, Toshio
AU  - Fujimoto T
FAU - Terada, Yukihiro
AU  - Terada Y
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20120723
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Brain-Derived Neurotrophic Factor)
RN  - 0 (Galectin 1)
RN  - 0 (Nerve Growth Factors)
RN  - EC 2.7.10.1 (Receptor, trkB)
SB  - IM
MH  - Brain-Derived Neurotrophic Factor/genetics/metabolism/pharmacology
MH  - Cell Line, Tumor
MH  - Cell Proliferation/drug effects
MH  - Female
MH  - Galectin 1/genetics/metabolism
MH  - Gene Expression
MH  - Humans
MH  - Leiomyosarcoma/genetics/metabolism
MH  - Nerve Growth Factors/genetics/metabolism
MH  - Receptor, trkB/antagonists & inhibitors/genetics/*metabolism
MH  - Sarcoma/genetics/*metabolism
MH  - *Signal Transduction/drug effects
MH  - Uterine Neoplasms/genetics/*metabolism
PMC - PMC3402458
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2012/08/23 06:00
MHDA- 2013/04/23 06:00
PMCR- 2012/07/23
CRDT- 2012/08/23 06:00
PHST- 2011/12/15 00:00 [received]
PHST- 2012/06/19 00:00 [accepted]
PHST- 2012/08/23 06:00 [entrez]
PHST- 2012/08/23 06:00 [pubmed]
PHST- 2013/04/23 06:00 [medline]
PHST- 2012/07/23 00:00 [pmc-release]
AID - PONE-D-11-25221 [pii]
AID - 10.1371/journal.pone.0041049 [doi]
PST - ppublish
SO  - PLoS One. 2012;7(7):e41049. doi: 10.1371/journal.pone.0041049. Epub 2012 Jul 23.