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.

Abstract

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.

• Authors: Chia-Hung Chou, Lin-Hung Wei, Min-Liang Kuo, Yun-Ju Huang, Kuo-Pao Lai, Chi-An Chen, Chang-Yao Hsieh
• Journal: Carcinogenesis (Carcinogenesis) Vol. 26 Issue 1 Pg. 45-52 (Jan 2005) ISSN: 0143-3334 [Print] England
• PMID: 15471896 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Interleukin-6
• Lysophospholipids
• NF-kappa B
• Proto-Oncogene Proteins
• AKT1 protein, human
• Protein Serine-Threonine Kinases
• Proto-Oncogene Proteins c-akt
• Heterotrimeric GTP-Binding Proteins
• lysophosphatidic acid

Topics

• Blotting, Western
• Cell Line, Tumor
• Electrophoretic Mobility Shift Assay
• Enzyme Activation (drug effects, physiology)
• Female
• Heterotrimeric GTP-Binding Proteins (metabolism)
• Humans
• Interleukin-6 (biosynthesis)
• Lysophospholipids (pharmacology)
• NF-kappa B (drug effects, metabolism)
• Ovarian Neoplasms (metabolism)
• Phosphatidylinositol 3-Kinases (drug effects, metabolism)
• Protein Serine-Threonine Kinases (drug effects, metabolism)
• Proto-Oncogene Proteins (drug effects, metabolism)
• Proto-Oncogene Proteins c-akt
• Reverse Transcriptase Polymerase Chain Reaction
• Signal Transduction (drug effects, physiology)
• Up-Regulation