The lysophosphatidic acid type 2 receptor is required for protection against radiation-induced intestinal injury.
OBJECTIVE
We recently identified lysophosphatidic acid (LPA) as a potent antiapoptotic agent for the intestinal epithelium. The objective of the present study was to evaluate the effect of octadecenyl thiophosphate (OTP), a novel rationally designed, metabolically stabilized LPA mimic, on radiation-induced apoptosis of intestinal epithelial cells in vitro and in vivo.


METHODS
The receptors and signaling pathways activated by OTP were examined in IEC-6 and RH7777 cell lines and wild-type and LPA(1) and LPA(2) knockout mice exposed to different apoptotic stimuli.


RESULTS
OTP was more efficacious than LPA in reducing gamma irradiation-, camptothecin-, or tumor necrosis factor alpha/cycloheximide-induced apoptosis and caspase-3-8, and caspase-9 activity in the IEC-6 cell line. In RH7777 cells lacking LPA receptors, OTP selectively protected LPA(2) but not LPA(1) and LPA(3) transfectants. In C57BL/6 and LPA(1) knockout mice exposed to 15 Gy gamma irradiation, orally applied OTP reduced the number of apoptotic bodies and activated caspase-3-positive cells but was ineffective in LPA(2) knockout mice. OTP, with higher efficacy than LPA, enhanced intestinal crypt survival in C57BL/6 mice but was without any effect in LPA(2) knockout mice. Intraperitoneally administered OTP reduced death caused by lethal dose (LD)(100/30) radiation by 50%.


CONCLUSIONS
Our data indicate that OTP is a highly effective antiapoptotic agent that engages similar prosurvival pathways to LPA through the LPA(2) receptor subtype.
Deng
Wenlin
W
Department of Physiology, University of Tennessee Health Sciences Center, Memphis, TN 38163, USA.
Shuyu
E
E
Tsukahara
Ryoko
R
Valentine
William J
WJ
Durgam
Gangadhar
G
Gududuru
Veeresa
V
Balazs
Louisa
L
Manickam
Venkatraman
V
Arsura
Marcello
M
VanMiddlesworth
Lester
L
Johnson
Leonard R
LR
Parrill
Abby L
AL
Miller
Duane D
DD
Tigyi
Gabor
G
D000284:Administration, Oral; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects*; D002460:Cell Line; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005260:Female; D019204:GTP-Binding Proteins / Q000502:physiology; D005720:Gamma Rays / Q000009:adverse effects; D005786:Gene Expression Regulation; D007274:Injections, Intraperitoneal; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000494:pharmacology; D009943:Organophosphorus Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D011833:Radiation Injuries, Experimental / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D049368:Receptors, Lysophosphatidic Acid / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
C431577:Ltap protein, mouse; D009419:Nerve Tissue Proteins; D009943:Organophosphorus Compounds; D049368:Receptors, Lysophosphatidic Acid; D014409:Tumor Necrosis Factor-alpha; C520653:octadecenyl thiophosphate; D019869:Phosphatidylinositol 3-Kinases; D020928:Mitogen-Activated Protein Kinases; D019204:GTP-Binding Proteins