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uPA/uPAR system activation drives a glycolytic phenotype in melanoma cells
Author(s) -
Laurenzana Anna,
Chillà Anastasia,
Luciani Cristina,
Peppicelli Silvia,
Biagioni Alessio,
Bianchini Francesca,
Tenedini Elena,
Torre Eugenio,
Mocali Alessandra,
Calorini Lido,
Margheri Francesca,
Fibbi Gabriella,
Del Rosso Mario
Publication year - 2017
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.30817
Subject(s) - urokinase receptor , cancer research , pi3k/akt/mtor pathway , glycolysis , biology , melanoma , integrin , fibronectin , protein kinase b , signal transduction , receptor , microbiology and biotechnology , extracellular matrix , endocrinology , biochemistry , metabolism
In this manuscript, we show the involvement of the uPA/uPAR system in the regulation of aerobic glycolysis of melanoma cells. uPAR over‐expression in human melanoma cells controls an invasive and glycolytic phenotype in normoxic conditions. uPAR down‐regulation by siRNA or its uncoupling from integrins, and hence from integrin‐linked tyrosine kinase receptors (IL‐TKRs), by an antagonist peptide induced a striking inhibition of the PI3K/AKT/mTOR/HIF1α pathway, resulting into impairment of glucose uptake, decrease of several glycolytic enzymes and of PKM2, a checkpoint that controls metabolism of cancer cells. Further, binding of uPA to uPAR regulates expression of molecules that govern cell invasion, including extracellular matrix metallo‐proteinases inducer (EMPPRIN) and enolase, a glycolytyc enzyme that also serves as a plasminogen receptor, thus providing a common denominator between tumor metabolism and phenotypic invasive features. Such effects depend on the α5β1‐integrin‐mediated uPAR connection with EGFR in melanoma cells with engagement of the PI3K‐mTOR‐HIFα pathway. HIF‐1α trans‐activates genes whose products mediate tumor invasion and glycolysis, thus providing the common denominator between melanoma metabolism and its invasive features. These findings unveil a unrecognized interaction between the invasion‐related uPAR and IL‐TKRs in the control of glycolysis and disclose a new pharmacological target (i.e., uPAR/IL‐TKRs axis) for the therapy of melanoma.