Targetingpyruvate kinase M2 isoform inhibits proliferation of human lung fibroblasts

Abstract

Background: Idiopathic Pulmonary Fibrosis (IPF) is a progressive interstitial lung disease of poor prognosis with a paucity of therapeutic options. Similarities between cancer cell biology and fibro-prolifortative pathomechanisms in fibrosis are becoming increasingly recognised, in particular the role of cell metabolism in driving these processes. Aims: A hallmark of certain tumours is their ability to anabolically fuel cell proliferation by aerobic glycolysis. Increased de novo expression of the glycolytic enzyme pyruvate kinase M2 (PKM2) central to this process, and targeting PKM2 with small molecules attenuates tumor cell proliferation and reduces tumorigenesis in animal models. We hypothesised aerobic glycolysis involving PKM2 may be important driving fibroblast proliferation. Methods: We investigated the role of PKM2 in supporting proliferation of primary human lung fibroblasts (HLF) in vitro, using the commercially available PKM2 activator TEPP-46 and the glucose analogue 2-deoxyglucose (2-DG) to dissect the metabolic demands of HLF during proliferation. Results: We show that PKM2 mRNA and protein is expressed in HLF. Treatment with the glucose analogue 2-Deoxy glucose or the PKM2 activator TEPP-46 significantly reduced HLF DNA synthesis over 72 hours in response to fetal calf serum or PDGF-stimulation, in a concentration-dependent manner. Conclusions: These data show that HLF express the key glycolytic enzyme PKM2 isoform, which can be targeted pharmacologically. Moreover, pharmacological manipulation of glucose metabolism indicates that glycolytic intermediates are critical for HLF proliferation.