title: Suppression of tunicamycin-induced CD44v6 ectodomain shedding and apoptosis             is correlated with temporal expression patterns of active ADAM10, MMP-9 and MMP-13             proteins in Caki-2 renal carcinoma cells.
abstract: CD44v6 has been shown to coordinate the activation of anti-apoptotic molecules as well as resistance to apoptosis. Here, we investigated CD44v6 ectodomain shedding in Caki-2 human renal carcinoma cells as well as its underlying mechanisms. Exposure of cells to tunicamycin (TM)-induced apoptosis was accompanied by cleavage of caspase-3, PARP-1 and CD44v6 ectodomain. TM-induced apoptosis was also closely associated with endoplasmic reticulum (ER) stress, as shown by increased expression of GRP-78 and CHOP proteins. Furthermore, induction of matrix metallo-proteinase (MMP)-13, MMP-9 and ADAM10 expression was highly stimulated by tunicamycin in a time- and dose-dependent manner. TM-induced PARP-1 cleavage was significantly inhibited by treatment with GM6001 (a broad spectrum MMP inhibitor), MMP-9/-13 inhibitor and GI254023X (specific ADAM10 inhibitor). In addition, inhibition of all examined MMPs resulted in reversal of TM-induced apoptosis as well as increased cell viability. When considering the functional implications of MMP-9 and ADAM10, it is likely that active MMP-9 and ADAM10 help regulate the cellular levels of CD44v6 through cleavage of CD44v6 ectodomain during TM-induced apoptosis of Caki-2 cells. Collectively, these findings suggest that multiple TM-induced MMPs may cooperate to induce apoptosis.
authors.affiliation: Department of Biology, Kyungpook National University, Daegu 702-701,                     Republic of Korea.
authors.forename: Yeoun-Hee
authors.initials: YH
authors.lastname: Kim
authors.forename: Jae-Chang
authors.initials: JC
authors.lastname: Jung
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism*; D000072197:ADAM10 Protein; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D017209:Apoptosis; D002292:Carcinoma, Renal Cell / Q000378:metabolism*; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D004151:Dipeptides / Q000494:pharmacology; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism*; D006877:Hydroxamic Acids / Q000494:pharmacology; D007680:Kidney Neoplasms / Q000378:metabolism; D053509:Matrix Metalloproteinase 13 / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors / Q000494:pharmacology; D008565:Membrane Proteins / Q000378:metabolism*; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D051742:Transcription Factor CHOP / Q000378:metabolism; D014415:Tunicamycin / Q000494:pharmacology
chemical_list: C555398:3-(formylhydroxyamino)-2-(3-phenyl-1-propyl)butanoic acid (2,2-dimethyl-1-methylcarbamoyl-1-propyl)amide; D000900:Anti-Bacterial Agents; C112697:CD44v6 antigen; C497249:DDIT3 protein, human; D004151:Dipeptides; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; D018960:Hyaluronan Receptors; D006877:Hydroxamic Acids; D061965:Matrix Metalloproteinase Inhibitors; D008565:Membrane Proteins; C078131:N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide; D014415:Tunicamycin; D051742:Transcription Factor CHOP; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D053829:Amyloid Precursor Protein Secretases; D053148:Caspase 3; D051722:ADAM Proteins; D053509:Matrix Metalloproteinase 13; D020780:Matrix Metalloproteinase 9; D000072197:ADAM10 Protein; C491236:ADAM10 protein, human