53 Regulation of Glycolysis and the Warburg Effect in Keloids Journal Articles uri icon

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abstract

  • Abstract Introduction Hypertrophic and keloid scarring are considered as major determinants for long-term outcomes and quality of life for burn survivors. Keloid development is predicated on prolonged local inflammation and altered glucose metabolism. Owing to its tumor-like dependence on glucose, we hypothesized that keloids would display the bioenergetics of cancer cells; namely, increased glucose uptake via Glut1 and upregulation of key glycolytic enzymes. Furthermore, burn patients who develop keloids potentially demonstrate early evidence of the aforementioned features compared to non-keloid patients. Therefore, elevated Glut1 expression could serve as a marker for keloid development in burn patients. Methods We enrolled 27 control burn patients with 39% ± 4% total body surface area (TBSA) burns. The keloid burn group included 9 burn patients with 47% ± 9% TBSA burns. Skin was obtained for histology, gene and protein expression at 0–17 days post-burn. Results Keloids have higher Glut1 expression compared to normal and burn skin (7.72 vs. 0.15, p< 0.001; 7.72 vs. 2.35, p< 0.05). Keloids also exhibit enhanced expression of critical glycolytic enzymes compared to burn skin at 7–10 days post-burn (HK2: 4.14 vs. 2.36, p< 0.001; PFK1: 6.51 vs. 3.83, p< 0.001; PFK2: 5.35 vs. 1.27, p< 0.001; PDK1: 5.50 vs. 4.31, p< 0.05; PKM2: 7.58 vs. 2.98, p< 0.001). A Glut1 time-course analysis in burn skin from non-keloid patients indicated a significant elevation at 7–10 days post-burn compared to normal skin (3.22 vs. 0.20, p< 0.01). Skin from keloid burn patients prior to development of keloids demonstrate higher Glut1 expression compared to skin from non-keloid controls when matched by days post-burn (40.5 vs. 0.58 at 0–2 days, p< 0.05). Conclusions Patients who develop post-burn keloids exhibit early risk factors prior to the development of keloids (e.g. elevated skin Glut1). Keloids have an augmented reliance on glycolysis compared to burn skin. Therefore, early identification and targeting glycolysis in susceptible patients is key. Applicability of Research to Practice Upregulation of glycolytic enzymes and transporters such as Glut1 may serve as keloid predictive markers. Identification of at-risk patients allows for a tailored treatment regimen that targets dysregulated glycolysis in these patients. Pharmaceutical agents like shikonin suppress multiple glycolytic steps, serving as an effective means to interfere with the proliferative capacity of keloids. Potentially, local shikonin administration could serve as a therapy in select patients exhibiting keloid risk factors.

publication date

  • March 3, 2020