Genetic Perturbation of Pyruvate Dehydrogenase Kinase 1 Modulates Growth, Angiogenesis and Metabolic Pathways in Ovarian Cancer Xenografts.

Carolina Venturoli,Giovanni Esposito,Matteo Curtarello,Angela Grassi,Martina Verza,Santina Venuto,Filippo Navaglia,Ilaria Piga,Stefano Indraccolo

doi:10.3390/cells10020325

Abstract

Pyruvate dehydrogenase kinase 1 (PDK1) blockade triggers are well characterized in vitro metabolic alterations in cancer cells, including reduced glycolysis and increased glucose oxidation. Here, by gene expression profiling and digital pathology-mediated quantification of in situ markers in tumors, we investigated effects of PDK1 silencing on growth, angiogenesis and metabolic features of tumor xenografts formed by highly glycolytic OC316 and OVCAR3 ovarian cancer cells. Notably, at variance with the moderate antiproliferative effects observed in vitro, we found a dramatic negative impact of PDK1 silencing on tumor growth. These findings were associated with reduced angiogenesis and increased necrosis in the OC316 and OVCAR3 tumor models, respectively. Analysis of viable tumor areas uncovered increased proliferation as well as increased apoptosis in PDK1-silenced OVCAR3 tumors. Moreover, RNA profiling disclosed increased glucose catabolic pathways—comprising both oxidative phosphorylation and glycolysis—in PDK1-silenced OVCAR3 tumors, in line with the high mitotic activity detected in the viable rim of these tumors. Altogether, our findings add new evidence in support of a link between tumor metabolism and angiogenesis and remark on the importance of investigating net effects of modulations of metabolic pathways in the context of the tumor microenvironment.

Highlights

Tumor cells commonly disclose higher rates of glycolysis than normal cells [1], a metabolic alteration known as the Warburg effect, which represents the best-known metabolic hallmark of cancer [2]
We recently described a set of metabolism-related markers which can be used to investigate by immunohistochemistry (IHC) the metabolic make-up of tumors and by profiling patient-derived ovarian cancer xenografts (PDX) samples we observed that expression of MCT4, a monocarboxylate transporter associated with glycolysis [13], was negatively associated with survival of mice bearing intraperitoneal tumors [14]
We investigated effects of Pyruvate dehydrogenase kinase (PDK) silencing on glycolysis

Summary

Introduction

Tumor cells commonly disclose higher rates of glycolysis than normal cells [1], a metabolic alteration known as the Warburg effect, which represents the best-known metabolic hallmark of cancer [2]. As the Warburg effect is associated with cell proliferation both in normal and cancer cells [9], this link could possibly explain the accelerated rate of tumor growth associated with highly glycolytic tumors. It could be speculated that soluble factors released by highly glycolytic tumor cells, such as lactic acid or an acidic pH, modulate the stromal microenvironment, contributing to promote angiogenesis and making it more favorable to tumor growth [10]. Lactate can be picked up by stromal cells, such as fibroblasts and macrophages, and used to feed oxidative phosphorylation [11].

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