PMID- 20106902
OWN - NLM
STAT- MEDLINE
DCOM- 20100416
LR  - 20211203
IS  - 1460-2180 (Electronic)
IS  - 0143-3334 (Linking)
VI  - 31
IP  - 4
DP  - 2010 Apr
TI  - Phospholipase D signaling pathway is involved in lung cancer-derived IL-8 
      increased osteoclastogenesis.
PG  - 587-96
LID - 10.1093/carcin/bgq030 [doi]
AB  - Bone is a frequent target of lung cancer metastasis, which is associated with 
      significant morbidity and a dismal prognosis. This study analyzed the soluble 
      factors secreted by lung cancer cells, which are responsible for increasing 
      osteoclast differentiation. Addition of recombinant human interleukin-8 (rhIL-8), 
      present in large amounts in A549-conditioned medium (CM) and NCI-H460-CM, 
      mimicked the inductive effect of A549-CM and NCI-H460-CM on osteoclastogenesis. 
      In contrast, depletion of interleukin-8 (IL-8) from A549-CM and NCI-H460-CM 
      decreased the osteoclastogenesis-inductive properties of A549-CM and NCI-H460-CM. 
      Induction of osteoclast differentiation by lung cancer-derived-CM and rhIL-8 was 
      associated with increased phospholipase D (PLD) activation, and the activations 
      of protein kinase C (PKC) alpha/betaII, extracellular signal-regulated kinase 
      (ERK) 1/2 and AKT/the mammalian target of rapamycin (mTOR). Blocking PLD by a 
      specific inhibitor significantly decreased osteoclast formation by inhibiting 
      PKCs activation and subsequently attenuating the phosphorylation of ERK1/2. PLD 
      inhibitor also completely decreased AKT and mTOR phosphorylation, whereas 
      phosphatidylinositol-3-kinase (PI3K) inhibitor only partially decreased mTOR 
      phosphorylation, suggesting that mTOR activation by PLD is through both 
      PI3K/AKT-dependent and PI3K/AKT-independent manner. In addition, blocking AKT and 
      ERK1/2 by a specific inhibitor also suppressed lung cancer-derived-CM and 
      rhIL-8-induced osteoclast differentiation. Moreover, treatment of peripheral 
      blood mononuclear cells with sera from invasive lung cancer patients increased 
      the formation of osteoclasts. Our study suggests that IL-8 or IL-8-mediated 
      PLD/PKC/ERK1/2 or PLD/AKT signaling is an attractive therapeutic target for 
      osteolytic bone metastases in lung cancer patients.
FAU - Hsu, Ya-Ling
AU  - Hsu YL
AD  - Graduate Institute of Medicine, Schoolof Medicine, College of Medicine, Kaohsiung 
      Medical University, 807 Kaohsiung, Taiwan.
FAU - Hung, Jen-Yu
AU  - Hung JY
FAU - Ko, Ying-Chin
AU  - Ko YC
FAU - Hung, Chih-Hsing
AU  - Hung CH
FAU - Huang, Ming-Shyan
AU  - Huang MS
FAU - Kuo, Po-Lin
AU  - Kuo PL
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20100127
PL  - England
TA  - Carcinogenesis
JT  - Carcinogenesis
JID - 8008055
RN  - 0 (Interleukin-8)
RN  - 0 (Intracellular Signaling Peptides and Proteins)
RN  - 0 (RANK Ligand)
RN  - 0 (TNFSF11 protein, human)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.11.13 (Protein Kinase C-alpha)
RN  - EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases)
RN  - EC 3.1.4.4 (Phospholipase D)
SB  - IM
MH  - Bone Neoplasms/secondary
MH  - Cells, Cultured
MH  - Extracellular Signal-Regulated MAP Kinases/physiology
MH  - Humans
MH  - Interleukin-8/*physiology
MH  - Intracellular Signaling Peptides and Proteins/physiology
MH  - Lung Neoplasms/*pathology
MH  - MAP Kinase Signaling System
MH  - Osteoclasts/*physiology
MH  - Phosphatidylinositol 3-Kinases/physiology
MH  - Phospholipase D/*physiology
MH  - Protein Kinase C-alpha/physiology
MH  - Protein Serine-Threonine Kinases/physiology
MH  - Proto-Oncogene Proteins c-akt/physiology
MH  - RANK Ligand/physiology
MH  - Signal Transduction/*physiology
MH  - TOR Serine-Threonine Kinases
EDAT- 2010/01/29 06:00
MHDA- 2010/04/17 06:00
CRDT- 2010/01/29 06:00
PHST- 2010/01/29 06:00 [entrez]
PHST- 2010/01/29 06:00 [pubmed]
PHST- 2010/04/17 06:00 [medline]
AID - bgq030 [pii]
AID - 10.1093/carcin/bgq030 [doi]
PST - ppublish
SO  - Carcinogenesis. 2010 Apr;31(4):587-96. doi: 10.1093/carcin/bgq030. Epub 2010 Jan 
      27.