期刊
INTERNATIONAL JOURNAL OF CANCER
卷 141, 期 6, 页码 1190-1200出版社
WILEY
DOI: 10.1002/ijc.30817
关键词
uPA/uPAR system; cancer cell metabolism; melanoma cells
类别
资金
- Associazione Italiana Ricerca sul Cancro (AIRC) [IG 2013 N. 14266]
- Ente Cassa di Risparmio di Firenze
- IstitutoToscanoTumori
- Fondazione Italiana Per la Ricerca sul Cancro (FIRC)
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/HIF1 alpha 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 alpha 5b1-integrin-mediated uPAR connection with EGFR in melanoma cells with engagement of the PI3K-mTOR-HIF alpha pathway. HIF1 alpha 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.
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