Abstract
A keloid is a fibroproliferative skin tumor. Proliferating keloid fibroblasts (KFs) demand active metabolic utilization. The contributing roles of glycolysis and glucose metabolism in keloid fibroproliferation remain unclear. This study aims to determine the regulation of glycolysis and glucose metabolism by glucose transporter-1 (GLUT-1), an essential protein to initiate cellular glucose uptake, in keloids and in KFs. Tissues of keloids and healthy skin were explanted for KFs and normal fibroblasts (NFs), respectively. GLUT-1 expression was measured by immunofluorescence, RT-PCR, and immunoblotting. The oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) were measured with or without WZB117, a GLUT-1 inhibitor. Reactive oxygen species (ROS) were assayed by MitoSOX immunostaining. The result showed that glycolysis (ECAR) was enhanced in KFs, whereas OCR was not. GLUT-1 expression was selectively increased in KFs. Consistently, GLUT-1 expression was increased in keloid tissue. Treatment with WZB117 abolished the enhanced ECAR, including glycolysis and glycolytic capacity, in KFs. ROS levels were increased in KFs compared to those in NFs. GLUT-1 inhibition suppressed not only the ROS levels but also the cell proliferation in KFs. In summary, the GLUT-1-dependent glycolysis and ROS production mediated fibroblast proliferation in keloids. GLUT1 might be a potential target for metabolic reprogramming to treat keloids.
Highlights
A keloid is a proliferative scar that extends beyond the original injury borders with excess fibroblast proliferation and increased collagen production [1]
Since increased extracellular acidification rate (ECAR) in the keloid fibroblasts (KFs) was associated with a reciprocal decrease in oxygen consumption rate (OCR), wwee nneexxtt aasskkeedd tthhee mmeecchhaanniissmm bbyy wwhhiicchh EECCAARR ((ggllyyccoollyyssiiss)) iiss eennhhaanncceedd iinn KKFFss
Whereas WZB117 treatment suppressed spare respiration capacity in both normal fibroblasts (NFs) and KFs (Figure 5F), the spare respiratory capacity was higher in KFs despite WZB117 treatment. These results suggest that KFs are fueled predominantly by glucose transporter-1 (GLUT-1) dependent glycolysis rather than mitochondrial oxidative phosphorylation (OXPHOS)
Summary
A keloid is a proliferative scar that extends beyond the original injury borders with excess fibroblast proliferation and increased collagen production [1] It appears as a red, indurated, disfiguring tumor and may be accompanied by intractable pruritus, pain, and even contractions. Available treatments for keloids are palliative in nature [5] and they tends to recur despite therapeutic interventions [6,7], causing profound functional and psychosocial sequelae [8]. This therapeutic challenge is partly attributed to the poor understanding of its pathogenesis. Positron emission tomography (PET) images in patients with keloids demonstrate that fluorodeoxyglucose (FDG) increases to compensate for increases in glucose uptake and energy consumption [17,18]
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