MYCN amplification occurs in about 20–25% of human neuroblastomas and characterizes the majority of the high-risk cases, which display less than 50% prolonged survival rate despite intense multimodal treatment. Somehow paradoxically, MYCN also sensitizes neuroblastoma cells to apoptosis, understanding the molecular mechanisms of which might be relevant for the therapy of MYCN amplified neuroblastoma. We recently reported that the apoptosis-sensitive phenotype induced by MYCN is linked to stabilization of p53 and its proapoptotic kinase HIPK2. In MYCN primed neuroblastoma cells, further activation of both HIPK2 and p53 by Nutlin-3 leads to massive apoptosis in vitro and to tumor shrinkage and impairment of metastasis in xenograft models. Here we report that Galectin-3 impairs MYCN-primed and HIPK2-p53-dependent apoptosis in neuroblastoma cells. Galectin-3 is broadly expressed in human neuroblastoma cell lines and tumors and is repressed by MYCN to induce the apoptosis-sensitive phenotype. Despite its reduced levels, Galectin-3 can still exert residual antiapoptotic effects in MYCN amplified neuroblastoma cells, possibly due to its specific subcellular localization. Importantly, Nutlin-3 represses Galectin-3 expression, and this is required for its potent cell killing effect on MYCN amplified cell lines. Our data further characterize the apoptosis-sensitive phenotype induced by MYCN, expand our understanding of the activity of MDM2-p53 antagonists and highlight Galectin-3 as a potential biomarker for the tailored p53 reactivation therapy in patients with high-risk neuroblastomas.
Bagatell R, Beck-Popovic M, London WB, Zhang Y, Pearson AD, et al. (2009) Significance of MYCN amplification in international neuroblastoma staging system stage 1 and 2 neuroblastoma: a report from the International Neuroblastoma Risk Group database. J Clin Oncol 27: 365–370.
Canete A, Gerrard M, Rubie H, Castel V, Di Cataldo A, et al. (2009) Poor survival for infants with MYCN-amplified metastatic neuroblastoma despite intensified treatment: the International Society of Paediatric Oncology European Neuroblastoma Experience. J Clin Oncol 27: 1014–1019.
Nara K, Kusafuka T, Yoneda A, Oue T, Sangkhathat S, et al. (2007) Silencing of MYCN by RNA interference induces growth inhibition, apoptotic activity and cell differentiation in a neuroblastoma cell line with MYCN amplification. Int J Oncol 30: 1189–1196.
Burkhart CA, Cheng AJ, Madafiglio J, Kavallaris M, Mili M, et al. (2003) Effects of MYCN antisense oligonucleotide administration on tumorigenesis in a murine model of neuroblastoma. J Natl Cancer Inst 95: 1394–1403.
Zornig M, Busch G, Beneke R, Gulbins E, Lang F, et al. (1995) Survival and death of prelymphomatous B-cells from N-myc/bcl-2 double transgenic mice correlates with the regulation of intracellular Ca2+ fluxes. Oncogene 11: 2165–2174.
Van Maerken T, Ferdinande L, Taildeman J, Lambertz I, Yigit N, et al. (2009) Antitumor activity of the selective MDM2 antagonist nutlin-3 against chemoresistant neuroblastoma with wild-type p53. J Natl Cancer Inst 101: 1562–1574.
Van Maerken T, Vandesompele J, Rihani A, De Paepe A, Speleman F (2009) Escape from p53-mediated tumor surveillance in neuroblastoma: switching off the p14(ARF)-MDM2-p53 axis. Cell Death Differ 16: 1563–1572.
Califice S, Castronovo V, Bracke M, van den Brule F (2004) Dual activities of galectin-3 in human prostate cancer: tumor suppression of nuclear galectin-3 vs tumor promotion of cytoplasmic galectin-3. Oncogene 23: 7527–7536.
Takenaka Y, Fukumori T, Yoshii T, Oka N, Inohara H, et al. (2004) Nuclear export of phosphorylated galectin-3 regulates its antiapoptotic activity in response to chemotherapeutic drugs. Molecular and cellular biology 24: 4395–4406.
Fukumori T, Oka N, Takenaka Y, Nangia-Makker P, Elsamman E, et al. (2006) Galectin-3 regulates mitochondrial stability and antiapoptotic function in response to anticancer drug in prostate cancer. Cancer Res 66: 3114–3119.
Cecchinelli B, Lavra L, Rinaldo C, Iacovelli S, Gurtner A, et al. (2006) Repression of the antiapoptotic molecule galectin-3 by homeodomain-interacting protein kinase 2-activated p53 is required for p53-induced apoptosis. Mol Cell Biol 26: 4746–4757.
Lavra L, Rinaldo C, Ulivieri A, Luciani E, Fidanza P, et al. (2011) The loss of the p53 activator HIPK2 is responsible for galectin-3 overexpression in well differentiated thyroid carcinomas. PLoS One 6: e20665.
Hopkins-Donaldson S, Yan P, Bourloud KB, Muhlethaler A, Bodmer JL, et al. (2002) Doxorubicin-induced death in neuroblastoma does not involve death receptors in S-type cells and is caspase-independent in N-type cells. Oncogene 21: 6132–6137.
Lutz W, Stohr M, Schurmann J, Wenzel A, Lohr A, et al. (1996) Conditional expression of N-myc in human neuroblastoma cells increases expression of alpha-prothymosin and ornithine decarboxylase and accelerates progression into S-phase early after mitogenic stimulation of quiescent cells. Oncogene 13: 803–812.
Giammarioli AM, Gambardella L, Barbati C, Pietraforte D, Tinari A, et al. (2012) Differential effects of the glycolysis inhibitor 2-deoxy-D-glucose on the activity of pro-apoptotic agents in metastatic melanoma cells, and induction of a cytoprotective autophagic response. International journal of cancer Journal international du cancer 131: E337–347.
Giannini G, Kim CJ, Marcotullio LD, Manfioletti G, Cardinali B, et al. (2000) Expression of the HMGI(Y) gene products in human neuroblastic tumours correlates with differentiation status. Br J Cancer 83: 1503–1509.
Giannini G, Di Marcotullio L, Ristori E, Zani M, Crescenzi M, et al. (1999) HMGI(Y) and HMGI-C genes are expressed in neuroblastoma cell lines and tumors and affect retinoic acid responsiveness. Cancer Res 59: 2484–2492.
Yu F, Finley RL Jr, Raz A, Kim HR (2002) Galectin-3 translocates to the perinuclear membranes and inhibits cytochrome c release from the mitochondria. A role for synexin in galectin-3 translocation. J Biol Chem 277: 15819–15827.
Bartolazzi A, Orlandi F, Saggiorato E, Volante M, Arecco F, et al. (2008) Galectin-3-expression analysis in the surgical selection of follicular thyroid nodules with indeterminate fine-needle aspiration cytology: a prospective multicentre study. Lancet Oncol 9: 543–549.
Bartolazzi A, Gasbarri A, Papotti M, Bussolati G, Lucante T, et al. (2001) Application of an immunodiagnostic method for improving preoperative diagnosis of nodular thyroid lesions. Lancet 357: 1644–1650.
Cooper DS, Doherty GM, Haugen BR, Kloos RT, Lee SL, et al. (2009) Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid 19: 1167–1214.
Reynolds CP, Tomayko MM, Donner L, Helson L, Seeger RC, et al. (1988) Biological classification of cell lines derived from human extra-cranial neural tumors. Progress in clinical and biological research 271: 291–306.