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
Department of Experimental and Clinical Biomedical Sciences, Section of Experimental Pathology and Oncology, University of Florence, Florence, 50134, Italy.
Center for Genome Research, Life Sciences Department, University of Modena, Modena, 41125, Italy.
Int J Cancer. 2017 Sep 15;141(6):1190-1200. doi: 10.1002/ijc.30817. Epub 2017 Jun 21.
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.
在本论文中，我们展示了尿激酶型纤溶酶原激活物（uPA）/尿激酶型纤溶酶原激活物受体（uPAR）系统参与黑色素瘤细胞有氧糖酵解的调控。人黑色素瘤细胞中uPAR的过表达在常氧条件下控制着侵袭性和糖酵解表型。通过小干扰RNA（siRNA）下调uPAR，或用拮抗剂肽使其与整合素解偶联，进而与整合素连接的酪氨酸激酶受体（IL-TKRs）解偶联，可显著抑制PI3K/AKT/mTOR/HIF1α信号通路，导致葡萄糖摄取受损、多种糖酵解酶及丙酮酸激酶M2（PKM2，一种控制癌细胞代谢的检查点）减少。此外，uPA与uPAR的结合调节了控制细胞侵袭的分子表达，包括细胞外基质金属蛋白酶诱导剂（EMPPRIN）和烯醇化酶（一种糖酵解酶，也作为纤溶酶原受体），从而在肿瘤代谢和表型侵袭特征之间提供了一个共同特征。这些效应取决于α5β1整合素介导的uPAR与黑色素瘤细胞中表皮生长因子受体（EGFR）的连接，并激活PI3K-mTOR-HIFα信号通路。缺氧诱导因子-1α（HIF-1α）反式激活其产物介导肿瘤侵袭和糖酵解的基因，从而在黑色素瘤代谢及其侵袭特征之间提供了共同特征。这些发现揭示了侵袭相关的uPAR与IL-TKRs在糖酵解控制中一种未被认识的相互作用，并揭示了黑色素瘤治疗的新药理学靶点（即uPAR/IL-TKRs轴）。
