Interleukin-6 signaling regulates anchorage-independent growth, proliferation, adhesion and invasion in human ovarian cancer cells

• Published in: Cytokine (Philadelphia, Pa.) Pa.), 2012-08, Vol.59 (2), p.228-236
• Main Authors: Wang, Yue, Li, Lingzhi, Guo, Xiaoqin, Jin, Xin, Sun, Weijia, Zhang, Xiaolei, Xu, Rui Cheng
• Format: Article
• Language: English
• Subjects: adhesion; Androstadienes - pharmacology; animal ovaries; apoptosis; Apoptosis - drug effects; ascites; blood serum; Cell Adhesion - drug effects; cell cycle; Cell Cycle - drug effects; Cell Line, Tumor; cell proliferation; Cell Proliferation - drug effects; Cell Transformation, Neoplastic - drug effects; Cell Transformation, Neoplastic - pathology; Female; Flavonoids - pharmacology; Gene Expression Regulation, Neoplastic - drug effects; gene overexpression; Humans; Interleukin-6; Interleukin-6 - metabolism; Interleukin-6 receptor; Matrix Metalloproteinase 2 - metabolism; Matrix Metalloproteinase 9 - metabolism; Neoplasm Invasiveness; Ovarian cancer; ovarian neoplasms; Ovarian Neoplasms - enzymology; Ovarian Neoplasms - genetics; Ovarian Neoplasms - pathology; patients; Phenotype; phosphorylation; Phosphorylation - drug effects; plasmids; prognosis; proteolysis; Proteolysis - drug effects; Ras/MEK/ERK and PI3K/Akt signaling; Receptors, Interleukin-6 - genetics; Receptors, Interleukin-6 - metabolism; signal transduction; Signal Transduction - drug effects; Tumorigenic properties
• ISSN: 1043-4666; 1096-0023
• DOI: 10.1016/j.cyto.2012.04.020

► We find that IL-6 secreted by OVCA cells promotes malignant behavior of these cells. ► IL-6 promotes OVCA cell proliferation by altering cell cycle distribution. ► IL-6 stimulates cell proliferation via activation of Raf/MEK/ERK and PI3K/Akt. ► IL-6-enhanced cell invasive correlates with increased MMP-9 but not MMP-2 activity. ► Regulation of IL-6 may be a promising strategy for controlling OVCA progression. It has been widely reported that Interleukin-6 (IL-6) is overexpressed in the serum and ascites of ovarian cancer (OVCA) patients, and elevated IL-6 level correlates with poor prognosis and survival. However, the exact role that IL-6 plays in this malignancy or whether IL-6 can regulate tumorigenic properties has not been established. Here we demonstrate that overexpression of IL-6 in non-IL-6-expressing A2780 cells (by transfecting with plasmid encoding for sense IL-6) increases anchorage-independent growth, proliferation, adhesion and invasion, while depletion of endogenous IL-6 expression in IL-6-overexpressing SKOV-3 cells (by transfecting with plasmid encoding for antisense IL-6) decreases. Further investigation indicates that IL-6 promotes OVCA cell proliferation by altering cell cycle distribution rather than inhibiting apoptosis and that IL-6-enhanced OVCA cell invasive may be associated with increased matrix metalloproteinase (MMP)-9 but not MMP-2 proteolytic activity. In addition, overexpressing or deleting of IL-6 in OVCA cells enhances or reduces its receptor (IL-6Rα and gp130) expression and basal phosphorylation levels of both ERK and Akt, and additional treatment with specific inhibitor of the ERK or Akt signaling pathway significantly inhibits the proliferation of IL-6-overexpressing A2780 cells. Our data suggest that the autocrine production of IL-6 by OVCA cells regulates tumorigenic properties of these cells by inducing IL-6 signaling pathways. Thus, regulation of IL-6 expression or its related signaling pathway may be a promising strategy for controlling the progression of OVCA.