Background: Most cancer cells, including those of melanoma, rely on aerobic glycolysis, which causes a chronic acidification of tumor microenvironment. In turn, acidosis induces a metabolic shift toward glutaminolysis and increases the apoptotic threshold of cancer cells, favoring malignant progression and onset of drug-resistant phenotypes. Bcl-2 gene expression undergoes an intricate post-transcriptional regulation. Among the regulators of Bcl-2 mRNA fate, we identified ζ- Crystallin (CryZ) and highlighted its alteration in leukemia cells. Beside Bcl-2, CryZ regulates the expression of glutaminase (GLS) and glutamate dehydrogenase (GDH), two major genes of glutaminolysis. Furthermore, it has been demonstrated that aspirin-like analgesics are potent inhibitors of CryZ enzymatic activity. Methods: Biomolecular effects of exogenous modulation, per se or in combination with targeted therapies, have been analyzed in A375 and MeWo melanoma cells exposed to extracellular acidosis. In addition, the role of acetylsalicylic acid (ASA) and salicylic acid (SA) on CryZ binding activity to mRNA targets has been investigated. Results: We demonstrated that: 1) acidosis induced the expression of CryZ; 2) inhibition of p38 pathway prevented acidosis-mediated CryZ upregulation; 3) acidosis conferred CryZ-dependent resistance to vemurafenib; 4) besides Bcl-2, CryZ associates with the anti-apoptotic Bcl-xL mRNA; 5) ASA and SA impaired the binding of CryZ to Bcl-2, BclxL and GLS mRNAs. Conclusions: We disclosed a role of CryZ as an important pH-responsive element that confers a cytoprotective effect on melanoma cells. In addition, the evidence that ASA and SA impaired CryZ binding to its mRNA targets could lay the basis for development of innovative posttranscriptional therapeutic tools.

Involvement of ζ-Crystallin in Acidic Microenvironment of Melanoma / Lulli, M.; Loffredo, R.; Lapucci, A.; Papucci, L.; Capaccioli, S.; Schiavone, N.. - In: THE AMERICAN JOURNAL OF PATHOLOGY. - ISSN 0002-9440. - ELETTRONICO. - 186:(2016), pp. 0-0.

Involvement of ζ-Crystallin in Acidic Microenvironment of Melanoma

LULLI, MATTEO;LOFFREDO, ROSA;LAPUCCI, ANDREA;PAPUCCI, LAURA;CAPACCIOLI, SERGIO;SCHIAVONE, NICOLA
2016

Abstract

Background: Most cancer cells, including those of melanoma, rely on aerobic glycolysis, which causes a chronic acidification of tumor microenvironment. In turn, acidosis induces a metabolic shift toward glutaminolysis and increases the apoptotic threshold of cancer cells, favoring malignant progression and onset of drug-resistant phenotypes. Bcl-2 gene expression undergoes an intricate post-transcriptional regulation. Among the regulators of Bcl-2 mRNA fate, we identified ζ- Crystallin (CryZ) and highlighted its alteration in leukemia cells. Beside Bcl-2, CryZ regulates the expression of glutaminase (GLS) and glutamate dehydrogenase (GDH), two major genes of glutaminolysis. Furthermore, it has been demonstrated that aspirin-like analgesics are potent inhibitors of CryZ enzymatic activity. Methods: Biomolecular effects of exogenous modulation, per se or in combination with targeted therapies, have been analyzed in A375 and MeWo melanoma cells exposed to extracellular acidosis. In addition, the role of acetylsalicylic acid (ASA) and salicylic acid (SA) on CryZ binding activity to mRNA targets has been investigated. Results: We demonstrated that: 1) acidosis induced the expression of CryZ; 2) inhibition of p38 pathway prevented acidosis-mediated CryZ upregulation; 3) acidosis conferred CryZ-dependent resistance to vemurafenib; 4) besides Bcl-2, CryZ associates with the anti-apoptotic Bcl-xL mRNA; 5) ASA and SA impaired the binding of CryZ to Bcl-2, BclxL and GLS mRNAs. Conclusions: We disclosed a role of CryZ as an important pH-responsive element that confers a cytoprotective effect on melanoma cells. In addition, the evidence that ASA and SA impaired CryZ binding to its mRNA targets could lay the basis for development of innovative posttranscriptional therapeutic tools.
2016
Lulli, M.; Loffredo, R.; Lapucci, A.; Papucci, L.; Capaccioli, S.; Schiavone, N.
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Utilizza questo identificatore per citare o creare un link a questa risorsa: https://hdl.handle.net/2158/1058829
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