Up-regulation of interleukin-6 in human ovarian cancer cell via a Gi/PI3K-Akt/NF-kappaB pathway by lysophosphatidic acid, an ovarian cancer-activating factor.
Bioactive lysophospholipid, lysophosphatidic acid (LPA), is consistently raised in the ascites of patients with ovarian cancer. Interleukin-6 (IL-6) is a pleiotropic cytokine, which is assumed to be involved in ovarian carcinogenesis. However, the regulation of IL-6 in ovarian cancer remains largely unknown. To elucidate the pathogenesis of ovarian cancer, this study investigated how LPA affects IL-6 production in ovarian cancer cells. Experimental results indicated that LPA stimulates IL-6 expression in all ovarian cancer cell lines tested, but not in normal ovarian surface epithelial (NOSE) cells, owing to the lack of LPA-specific Edg4 and/or Edg7 receptors in NOSE cells. This work demonstrated that LPA transcriptionally activates IL-6 expression, which can be totally blocked by the pertussis toxin, indicating that Gi-mediated signaling is critically involved in inducing IL-6 by LPA. Pharmacological and genetic inhibition assays revealed that Gi-mediated PI3K activation phosphorylated downstream Akt and subsequently induced NF-kappaB activation causes the induction of IL-6 by LPA in SK-OV-3 cells. In summary, data presented here demonstrate that LPA is an important inducer of IL-6 and LPA-regulated IL-6 expression via a Gi/PI3K-Akt/NF-kappaB pathway in ovarian cancer cells, providing molecular therapeutic targets for treating ovarian cancer.
Laboratory of Molecular and Cellular Toxicology, Institute of Toxicology, National Taiwan University College of Medicine, Taipei, Taiwan.
Chia-Hung
CH
Chou
Lin-Hung
LH
Wei
Min-Liang
ML
Kuo
Yun-Ju
YJ
Huang
Kuo-Pao
KP
Lai
Chi-An
CA
Chen
Chang-Yao
CY
Hsieh
D015153:Blotting, Western; D045744:Cell Line, Tumor; D024202:Electrophoretic Mobility Shift Assay; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D005260:Female; D020962:Heterotrimeric GTP-Binding Proteins / Q000378:metabolism; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis*; D008246:Lysophospholipids / Q000494:pharmacology*; D016328:NF-kappa B / Q000187:drug effects / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000187:drug effects / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000187:drug effects / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000187:drug effects / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D015854:Up-Regulation
D020962:Heterotrimeric GTP-Binding Proteins; D015850:Interleukin-6; D008246:Lysophospholipids; D016328:NF-kappa B; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; C494918:AKT1 protein, human; C032881:lysophosphatidic acid