title: Tumor necrosis factor-alpha differentially modulates CD44 expression in ovarian cancer cells.
abstract: Chronic inflammation is implicated in the pathophysiology of ovarian cancer. Tumor necrosis factor-alpha (TNF-alpha), a major inflammatory cytokine, is abundant in the ovarian cancer microenvironment. TNF-alpha modulates the expression of CD44 in normal T lymphocytes and CD44 is implicated in ovarian carcinogenesis and metastases. However, little is known about the role of TNF-alpha in CD44 expression of cancer cells. Recent clinical work using TNF-alpha inhibitors for the treatment of ovarian cancer makes the study of TNF-alpha interactions with CD44 crucial to determining treatment a success or a failure. We studied the effect of TNF-alpha on ovarian cancer cells viability, CD44 expression, and in vitro migration/invasion. Our results revealed that TNF-alpha differentially modulates the expression of CD44 in TNF-alpha-resistant ovarian cancer cells, affecting their in vitro migration, invasion, and binding to hyaluronic acid. TNF-alpha up-regulation of CD44 expression was dependent on the activation of c-Jun NH(2)-terminal kinase (JNK) and this activation was accompanied by an increase in their invasive phenotype. On the contrary, if TNF-alpha failed to induce JNK phosphorylation, the end result was down-regulation of both CD44 expression and the invasive phenotype. These results were confirmed by the use of JNK inhibitors and a TNF receptor competitive inhibitor.
authors.affiliation: Division of Gynecologic Oncology, The Cancer Institute of New Jersey, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, Room 2009, 195 Little Albany Street, New Brunswick, 08901, USA.
authors.forename: Neelakandan
authors.initials: N
authors.lastname: Muthukumaran
authors.forename: Karl E
authors.initials: KE
authors.lastname: Miletti-González
authors.forename: Abhilash K
authors.initials: AK
authors.lastname: Ravindranath
authors.forename: Lorna
authors.initials: L
authors.lastname: Rodríguez-Rodríguez
mesh_terms: D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003094:Collagen / Q000187:drug effects; D004338:Drug Combinations; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism*; D006820:Hyaluronic Acid / Q000378:metabolism; D007797:Laminin / Q000187:drug effects; D009361:Neoplasm Invasiveness; D010051:Ovarian Neoplasms / Q000378:metabolism*; D011509:Proteoglycans / Q000187:drug effects; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000494:pharmacology*
chemical_list: C497483:CD44 protein, human; D004338:Drug Combinations; D018960:Hyaluronan Receptors; D007797:Laminin; D011509:Proteoglycans; D014409:Tumor Necrosis Factor-alpha; C059485:matrigel; D006820:Hyaluronic Acid; D003094:Collagen; D048049:Extracellular Signal-Regulated MAP Kinases