Lysophosphatidic acid (LPA) in malignant ascites stimulates motility of human pancreatic cancer cells through LPA1.
Cytokines and growth factors in malignant ascites are thought to modulate a variety of cellular activities of cancer cells and normal host cells. The motility of cancer cells is an especially important activity for invasion and metastasis. Here, we examined the components in ascites, which are responsible for cell motility, from patients and cancer cell-injected mice. Ascites remarkably stimulated the migration of pancreatic cancer cells. This response was inhibited or abolished by pertussis toxin, monoglyceride lipase, an enzyme hydrolyzing lysophosphatidic acid (LPA), and Ki16425 and VPC12249, antagonists for LPA receptors (LPA1 and LPA3), but not by an LPA3-selective antagonist. These agents also inhibited the response to LPA but not to the epidermal growth factor. In malignant ascites, LPA is present at a high level, which can explain the migration activity, and the fractionation study of ascites by lipid extraction and subsequent thin-layer chromatography indicated LPA as an active component. A significant level of LPA1 receptor mRNA is expressed in pancreatic cancer cells with high migration activity to ascites but not in cells with low migration activity. Small interfering RNA against LPA1 receptors specifically inhibited the receptor mRNA expression and abolished the migration response to ascites. These results suggest that LPA is a critical component of ascites for the motility of pancreatic cancer cells and LPA1 receptors may mediate this activity. LPA receptor antagonists including Ki16425 are potential therapeutic drugs against the migration and invasion of cancer cells.
Yamada
Takayuki
T
Laboratory of Signal Transduction, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi 371-8512, Japan.
Sato
Koichi
K
Komachi
Mayumi
M
Malchinkhuu
Enkhzol
E
Tobo
Masayuki
M
Kimura
Takao
T
Kuwabara
Atsushi
A
Yanagita
Yasuhiro
Y
Ikeya
Toshiro
T
Tanahashi
Yoshifumi
Y
Ogawa
Tetsushi
T
Ohwada
Susumu
S
Morishita
Yasuo
Y
Ohta
Hideo
H
Im
Doon-Soon
DS
Tamoto
Koichi
K
Tomura
Hideaki
H
Okajima
Fumikazu
F
D000328:Adult; D000818:Animals; D001201:Ascites / Q000378:metabolism*; D015152:Blotting, Northern; D002448:Cell Adhesion; D002455:Cell Division; D045744:Cell Line, Tumor; D002465:Cell Movement; D002855:Chromatography, Thin Layer; D004305:Dose-Response Relationship, Drug; D004815:Epidermal Growth Factor / Q000378:metabolism; D005260:Female; D006801:Humans; D007555:Isoxazoles / Q000494:pharmacology; D008055:Lipids; D008246:Lysophospholipids / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008875:Middle Aged; D008994:Monoacylglycerol Lipases / Q000494:pharmacology; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D010190:Pancreatic Neoplasms / Q000378:metabolism*; D037342:Pertussis Toxin / Q000494:pharmacology; D011422:Propionates / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D049368:Receptors, Lysophosphatidic Acid; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014162:Transfection
C477898:3-(4-(4-((1-(2-chlorophenyl)ethoxy)carbonyl amino)-3-methyl-5-isoxazolyl) benzylsulfanyl) propanoic acid; D007555:Isoxazoles; D008055:Lipids; D008246:Lysophospholipids; D011422:Propionates; D012333:RNA, Messenger; D043562:Receptors, G-Protein-Coupled; D049368:Receptors, Lysophosphatidic Acid; D004815:Epidermal Growth Factor; D037342:Pertussis Toxin; D008994:Monoacylglycerol Lipases