Mechanisms for lysophosphatidic acid-induced cytokine production in ovarian cancer cells.
A potential role for lysophosphatidic acid (LPA) in human oncogenesis was first suggested by the observation that LPA is present at elevated levels in ascites of ovarian cancer patients. In the current study, we demonstrated that LPA is a potent inducer of interleukin-6 (IL-6) and interleukin-8 (IL-8) production in ovarian cancer cells. Both IL-6 and IL-8 have been implicated in ovarian cancer progression. We characterized the IL-8 gene promoter to ascertain the transcriptional mechanism underlying LPA -induced expression of these cytokines. LPA stimulated the transcriptional activity of the IL-8 gene with little effect on IL-8 mRNA stability. The optimal response of the IL-8 gene promoter to LPA relied on binding sites for NF-kappaB and AP-1, two transcription factors that were strongly activated by LPA in ovarian cancer cell lines. Positive regulators of the NF-kappaB and AP-1 pathways synergistically activated the IL-8 gene promoter. Further, the effect of LPA on IL-6 and IL-8 generation is mediated by the Edg LPA receptors as enforced expression of LPA receptors restored LPA-induced IL-6 and IL-8 production in non-responsive cells and enhanced the sensitivity to LPA in responsive cell lines. The LPA(2) receptor was identified to be the most efficient in linking LPA to IL-6 and IL-8 production although LPA(1) and LPA(3) were also capable of increasing the response to a certain degree. These studies elucidate the transcriptional mechanism and the Edg LPA receptors involved in LPA-induced IL-6 and IL-8 production and suggest potential strategies to restrain the expression of these cytokines in ovarian cancer.
Fang
Xianjun
X
Department of Molecular Therapeutics, M. D. Anderson Cancer Center, Houston, Texas 77030, USA. xfang@vcu.edu
Yu
Shuangxing
S
Bast
Robert C
RC
Liu
Shuying
S
Xu
Hong-Ji
HJ
Hu
Shi-Xue
SX
LaPushin
Ruth
R
Claret
Francois X
FX
Aggarwal
Bharat B
BB
Lu
Yiling
Y
Mills
Gordon B
GB
D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000235:genetics; D016209:Interleukin-8 / Q000096:biosynthesis* / Q000235:genetics; D008246:Lysophospholipids / Q000494:pharmacology*; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D049368:Receptors, Lysophosphatidic Acid; D015533:Transcriptional Activation / Q000187:drug effects
D015850:Interleukin-6; D016209:Interleukin-8; D008246:Lysophospholipids; D043562:Receptors, G-Protein-Coupled; D049368:Receptors, Lysophosphatidic Acid; C032881:lysophosphatidic acid