SOX2 as a novel contributor of oxidative metabolism in melanoma cells

Elena Andreucci,Lido Calorini,Francesca Bianchini,Barbara Stecca,Silvia Pietrobono,Alessio Biagioni,Silvia Peppicelli,Jessica Ruzzolini

doi:10.1186/s12964-018-0297-z

Abstract

BackgroundDeregulated metabolism is a hallmark of cancer and recent evidence underlines that targeting tumor energetics may improve therapy response and patient outcome. Despite the general attitude of cancer cells to exploit the glycolytic pathway even in the presence of oxygen (aerobic glycolysis or “Warburg effect”), tumor metabolism is extremely plastic, and such ability to switch from glycolysis to oxidative phosphorylation (OxPhos) allows cancer cells to survive under hostile microenvironments. Recently, OxPhos has been related with malignant progression, chemo-resistance and metastasis. OxPhos is induced under extracellular acidosis, a well-known characteristic of most solid tumors, included melanoma.MethodsTo evaluate whether SOX2 modulation is correlated with metabolic changes under standard or acidic conditions, SOX2 was silenced and overexpressed in several melanoma cell lines. To demonstrate that SOX2 directly represses HIF1A expression we used chromatin immunoprecipitation (ChIP) and luciferase assay.ResultsIn A375-M6 melanoma cells, extracellular acidosis increases SOX2 expression, that sustains the oxidative cancer metabolism exploited under acidic conditions. By studying non-acidic SSM2c and 501-Mel melanoma cells (high- and very low-SOX2 expressing cells, respectively), we confirmed the metabolic role of SOX2, attributing SOX2-driven OxPhos reprogramming to HIF1α pathway disruption.ConclusionsSOX2 contributes to the acquisition of an aggressive oxidative tumor phenotype, endowed with enhanced drug resistance and metastatic ability.

Highlights

Deregulated metabolism is a hallmark of cancer and recent evidence underlines that targeting tumor energetics may improve therapy response and patient outcome
To evaluate the activity of pyruvate dehydrogenase (PDH) enzyme, which drives the pyruvate enter into tricarboxylic acid cycle (TCA) cycle linking glycolysis to oxidative phosphorylation (OxPhos), we tested the expression of two enzymes that regulate PDH: the activating pyruvate dehydrogenase phosphatase 2 (PDP2) and the inhibiting pyruvate dehydrogenase kinase 1 (PDK1)
Despite significant variations were obtained only under acidic condition, we believe that monocarboxylate transporter 1 (MCT1) reduction with an unchanged level of monocarboxylate transporter 4 (MCT4) observed in standard condition might be indicative of a net lactate discharge

Summary

Introduction

Deregulated metabolism is a hallmark of cancer and recent evidence underlines that targeting tumor energetics may improve therapy response and patient outcome. The reduction in oxygen tension that characterizes proliferating tumor tissues, stimulates the hypoxia-inducible factor α (HIF1α), which drives the anaerobic glycolysis. This leads to lactate dehydrogenase A (LDH-A)-dependent lactic acid production, and the upregulation of monocarboxylated transporter (MCT) and of sodium-proton exporters to avoid intracellular acidosis. While normal differentiated adult cells show pHi of ∼7.2 and pHe of ∼7.4, cancer cells have a higher pHi (> 7.4) and a lower pHe (6.7–7.1) This ‘reversed’ pH gradient creates a perfect storm for metastatic progression [5] by promoting malignant phenotype endowed with apoptosis resistance, radio- and chemotherapy resistance, immune surveillance escape programs, increased migration and ability of secondary organs colonization [6]. We have recently reported that acidic cancer cells undergo a metabolic change characterized by the acquisition of a more OxPhos phenotype through the inhibition of HIF1α expression, associated with a reduced proliferation compared to standard pH condition [7]

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Conclusion