title: Signaling pathways required for matrix metalloproteinase-9 induction by betacellulin in head-and-neck squamous carcinoma cells.
abstract: The mechanisms by which c-erbB-dependent signaling contribute to the invasive potential of HNSCC remain to be fully elucidated. We have previously shown that c-erbB autocrine and/or paracrine stimulation upregulates MMP-9 but has no effect on the related gelatinase, MMP-2. BTC, a major c-erbB ligand, has the ability to efficiently activate all c-erbB receptors and to bind directly to EGFR and c-erbB-4. BTC is commonly expressed in HNSCC cells and exerts the most potent effects in terms of MMP induction relative to other c-erbB ligands so far tested. In the present study, we explored the contribution of major downstream events triggered by BTC/c-erbB receptor signaling to the regulation of MMP-9 and in vitro invasiveness of HNSCC cells. In human HNSCC cell lines, SIHN-006 and Detroit-562, BTC treatment resulted in rapid tyrosine phosphorylation of all c-erbB receptors whereas both endogenous MMP-9 and BTC-stimulated MMP-9 were predominantly mediated via EGFR. BTC induced ERK1/2, JNK/SAPK and Akt phosphorylation with differing kinetics but not p38 kinase. The BTC-dependent activation of JNK and PI3K/Akt pathways occurred predominantly via EGFR, whereas activation of the MEK-1/ERK pathway occurred via all 4 c-erbB receptors, although again predominantly via EGFR. Selective inhibition of ERK/MAPK (by PD98059 or U0126) and PI3K (by LY294002 or wortmannin) led to marked reduction of both basal and BTC-induced MMP-9 activity and invasive ability of HNSCC cells. In contrast, inhibition of p38 kinase with SB203580 produced no such effects. A specific inhibitor of NF-kappa B, BAY 11-7085, also blocked the stimulatory effect of BTC. No remarkable inhibition of MMP-9 and invasion was observed on targeting other cellular activities, such as PKA, PKC and PLC-gamma. Taken together, our data show that BTC induces MMP-9 production and invasion primarily through activation of EGFR, MAPK and PI3K/Akt in HNSCC cells.
authors.affiliation: Division of Head and Neck Surgery, Department of Surgery, Siriraj Hospital Medical School, Bangkok, Thailand. dipoc@mahidol.ac.th
authors.forename: Pornchai
authors.initials: P
authors.lastname: O-charoenrat
authors.forename: Adisak
authors.initials: A
authors.lastname: Wongkajornsilp
authors.forename: Peter H
authors.initials: PH
authors.lastname: Rhys-Evans
authors.forename: Suzanne A
authors.initials: SA
authors.lastname: Eccles
mesh_terms: D066259:Betacellulin; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000503:physiopathology*; D004790:Enzyme Induction; D004815:Epidermal Growth Factor; D066246:ErbB Receptors / Q000502:physiology; D018815:Genes, erbB; D006258:Head and Neck Neoplasms / Q000235:genetics* / Q000503:physiopathology*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology*; D020780:Matrix Metalloproteinase 9 / Q000494:pharmacology*; D020928:Mitogen-Activated Protein Kinases / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt; D015398:Signal Transduction
chemical_list: C587851:BTC protein, human; D066259:Betacellulin; D036341:Intercellular Signaling Peptides and Proteins; D011518:Proto-Oncogene Proteins; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases; D020780:Matrix Metalloproteinase 9