Abstract
Increased metabolism distinguishes myofibroblasts or fibrotic lung fibroblasts (fLfs) from the normal lung fibroblasts (nLfs). The mechanism of metabolic activation in fLfs has not been fully elucidated. Furthermore, the antifibrogenic effects of caveolin-1 scaffolding domain peptide CSP/CSP7 involving metabolic reprogramming in fLfs are unclear. We therefore analyzed lactate and succinate levels, as well as the expression of glycolytic enzymes and hypoxia inducible factor-1α (HIF-1α). Lactate and succinate levels, as well as the basal expression of glycolytic enzymes and HIF-1α, were increased in fLfs. These changes were reversed following restoration of p53 or its transcriptional target microRNA-34a (miR-34a) expression in fLfs. Conversely, inhibition of basal p53 or miR-34a increased glucose metabolism, glycolytic enzymes, and HIF-1α in nLfs. Treatment of fLfs or mice having bleomycin- or Ad-TGF-β1–induced lung fibrosis with CSP/CSP7 reduced the expression of glycolytic enzymes and HIF-1α. Furthermore, inhibition of p53 or miR-34a abrogated CSP/CSP7-mediated restoration of glycolytic flux in fLfs in vitro and in mice with pulmonary fibrosis and lacking p53 or miR-34a expression in fibroblasts in vivo. Our data indicate that dysregulation of glucose metabolism in fLfs is causally linked to loss of basal expression of p53 and miR-34a. Treatment with CSP/CSP7 constrains aberrant glucose metabolism through restoration of p53 and miR-34a.
Highlights
Glucose metabolism begins with its conversion to pyruvate through sequences of biochemical reactions termed glycolysis
We found that both lactate (Figure 1A) and succinate (Figure 1B) levels were significantly increased in human fLfs (hfLfs) and mouse fLfs (mfLfs) when compared with their expression in corresponding normal lung fibroblasts (nLfs)
We found that glycolytic enzymes such as hexokinase-2 (HK2), pyruvate kinase (PKM), phosphofructokinase (PFKP), and 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) levels were markedly upregulated in mfLfs and hfLfs (Figure 1D)
Summary
Glucose metabolism begins with its conversion to pyruvate through sequences of biochemical reactions termed glycolysis. The major shift to aerobic glycolysis with lactate production, with increased uptake of glucose, is likely used by proliferating carcinoma cells to promote the efficient conversion of glucose into the macromolecules required for increased cellular mass [7, 8]. This metabolic change, termed the Warburg effect, is a key event during tumor progression [9, 10]. A relative deficiency of caveolin-1 (CAV1) in tumor-associated fibroblasts has been postulated to underlie the reverse Warburg effect, in which cancer cell oxidants downregulate CAV1 in stromal fibroblasts that are tumorigenic in breast cancers [11, 12]
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