Galectin-3, a ubiquitous member of the galectin family, has been shown to control cellular proliferation, adhesion, migration and apoptosis; thus, it has a role in tumor development and progression. Galectin-3 expression is both up- and down-regulated during melanoma progression. However, conflicting data regarding its roles in tumor biology prompted us to investigate if the presence of galectin-3 influences the response of melanoma cells to a novel metallodrug because metastatic melanoma acquires chemo resistance and is reported to be redox-sensitive. Previously, it was demonstrated that the complex [bis-(2-oxindol-3-yl-imino)-2-(2-aminoethyl) pyridine-N,N'] copper (II) perchlorate, herein referred to as [Cu(isaepy)], induces ROS formation and apoptosis in neuroblastoma cells through mitochondrial uncoupling and the activation of AMPK/p38/p53 signaling. Here, we used a model of vertical growth melanoma (TM1), in which GAL3 expression is lost during tumor progression. When de novo expressed, galectin-3 was found to be ubiquitously present in all subcellular compartments. Our results demonstrate that de novo galectin-3 expression impairs the cellular antioxidant system and renders TM1G3 cells more susceptible than GAL3-null TM1MNG3 cells to [Cu(isaepy)] treatment. This compound, in contrast with the redox inactive [dichloro (2-oxindol-3-yl-imino)-2-(2-aminoethyl) pyridine-N,N'] zinc (II), herein referred to as [Zn(isaepy)], leads to increased intracellular ROS accumulation, increased carbonyl stress, increased mitochondrial depolarization, decreased cell adhesion, increased p38 activation and apoptosis in TM1G3, compared with TM1MNG3. Cell death was shown to be dependent on a hydrogen peroxide-derived species and on the activation of p38. Because mitochondria are a target of both [Cu(isaepy)] and galectin-3, we propose that the presence of galectin-3 in this organelle favors increased ROS production, thereby inducing oxidative cellular damage and apoptotic death. Therefore, [Cu(isaepy)] may be envisaged as a possible anti-melanoma strategy, particularly for melanomas that express galectin-3.
Keywords: 1-(4,5-dimethylthiazol-2-yl)-3,5-diphenylformazan; 1-chloro-2,4-dinitrobenzene; 2′,7′,dichlorodihydro fluorescein diacetate; 4′,6-Diamidino-2-phenylindole dihydrochloride; 5,5′-dithiobis (2-nitrobenzoic acid); AMPK; CAT; CDNB; Copper; DAPI; DCFH(2)-DA; DTNB; ECM; GST; Galectin-3; HRP; MTT; Melanoma cells; Metal complex; Peg; PrPc; ROS; SOD; [Cu(isaepy)(2)](ClO(4))(2); [Zn(isaepy)Cl(2)]; [bis-(2-oxindol-3-yl-imino)-2-(2-aminoethyl) pyridine-N,N’] copper (II) perchlorate; [dichloro (2-oxindol-3-yl-imino)-2-(2-aminoethyl) pyridine-N,N′] zinc (II); adenosine monophosphate-activated protein kinase; catalase; cellular prion protein; extracellular matrix; glutathione-S-transferase; horseradish peroxidase; polyethylene glycol; reactive oxygen species; superoxide dismutase.
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