Hepatocyte growth factor inhibits anoikis by induction of activator protein 1-dependent cyclooxygenase-2. Implication in head and neck squamous cell carcinoma progression.
Anoikis, also called suspension-induced apoptosis, plays an important role in tumor development, progression, and metastasis. Recently we found that hepatocyte growth factor (HGF) inhibited anoikis of human head and neck squamous cell carcinoma (HNSCC) cells by activating the extracellular signal-regulated kinase (ERK)-signaling pathway. However, the anti-apoptotic effectors that were regulated by the ERK-signaling pathway were unknown. Here we report that HGF-mediated inhibition of anoikis was dependent on activator protein-1 activity through the activation of the ERK-signaling pathway. Using a combination of microarray analysis and Northern blot analysis, we found that an anti-apoptotic gene cyclooxygenase-2 (cox-2) was induced by HGF in an activator protein-1-dependent fashion. Inhibition of Cox-2 activity partially abolished HGF-mediated cell survival, and overexpression of Cox-2 in HNSCC cells provided resistance against anoikis. Moreover, HNSCC cells stably expressing Cox-2 had aggressive tumor growth in a nude mouse model compared with control cells. Taken together, our results demonstrate that Cox-2 plays an important role in HGF-mediated anoikis resistance. HGF may stimulate the progression and growth of HNSCC in vivo by induction of Cox-2.
Zeng
Qinghua
Q
Laboratory of Molecular Signaling and Apoptosis, Department of Biologic and Materials Sciences, School of Dentistry and Medicine, University of Michigan, 1011 N. University Avenue, Ann Arbor, MI 48109-1078, USA.
McCauley
Laurie K
LK
Wang
Cun-Yu
CY
D000818:Animals; D023102:Anoikis; D017209:Apoptosis; D015152:Blotting, Northern; D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000378:metabolism*; D002455:Cell Division; D002470:Cell Survival; D051546:Cyclooxygenase 2; D018450:Disease Progression; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006258:Head and Neck Neoplasms / Q000378:metabolism*; D017228:Hepatocyte Growth Factor / Q000494:pharmacology*; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism*; D008565:Membrane Proteins; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009578:Nitrobenzenes / Q000494:pharmacology; D020411:Oligonucleotide Array Sequence Analysis; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D012190:Retroviridae / Q000235:genetics; D015398:Signal Transduction; D013449:Sulfonamides / Q000494:pharmacology; D013997:Time Factors; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D014158:Transcription, Genetic; D014161:Transduction, Genetic; D014407:Tumor Cells, Cultured
D004791:Enzyme Inhibitors; D007527:Isoenzymes; D008565:Membrane Proteins; D009578:Nitrobenzenes; D013449:Sulfonamides; D018808:Transcription Factor AP-1; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D017228:Hepatocyte Growth Factor; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases