GLUT-1 Enhances Glycolysis, Oxidative Stress, and Fibroblast Proliferation in Keloid

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.

Integrated Analysis of Cancer Tissue and Vitreous Humor from Retinoblastoma Eyes Reveals Unique Tumor-Specific Metabolic and Cellular Pathways in Advanced and Non-Advanced Tumors

“…Strikingly, we also identified the mitochondrial TCA-related FAHD1 gene [19] (p < 0.05, FC = 2.38) to be significantly upregulated in Rb subjects. The top downregulated genes comprised photoreceptor-related genes such as RHO [20] (p < 0.05, FC = −1058.9), NRL [21] (p < 0.05, FC = −104.00), PDE6D [22] (p < 0.05, FC = −7.178), CRABP1 [23] (p < 0.05, FC = −140.60), and glycolytic factors such as HK1 [24] (p < 0.05, FC = −17.46), SLC2A1 [25] (p < 0.05, FC = −8.16), and FOXO3 [26] (p < 0.05, FC = −5.08). The methyltransferase MGMT [27] (p < 0.05, FC = −4.8) and RB1 (p < 0.05, FC = −4.36) were significantly downregulated in Rb tumors.…”

The WWOX/HIF1A Axis Downregulation Alters Glucose Metabolism and Predispose to Metabolic Disorders

“…In skeletal muscle cells, a decrease of GLUT1-mediated glucose transport causes increased = ROS, whereas an increased glucose transport would result in decreased ROS levels [ 75 ]. Unlike that, the proliferating keloid fibroblasts (KFs) and showed that GLUT1 expression and ROS levels were increased in keloid tissue compared to normal fibroblasts [ 76 ]. GLUT1 inhibition suppressed the ROS levels in KFs [ 76 ].…”

“…Unlike that, the proliferating keloid fibroblasts (KFs) and showed that GLUT1 expression and ROS levels were increased in keloid tissue compared to normal fibroblasts [ 76 ]. GLUT1 inhibition suppressed the ROS levels in KFs [ 76 ]. This was not directly investigated but it is worth mentioning that oxidative stress plays a role in the pathogenesis and development of diabetes complications [ 77 ].…”

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“…Besides apoptosis, oxidative stress contributes to brain injury after SAH [ 68 ]. Inside the cells, the electric chain of mitochondrial oxidative phosphorylation is the predominant source of ROS [ 69 ]. Excessive ROS production induces DNA damage, and the resulting oxidative stress environments further exacerbate the cell damages [ 70 ].…”