Sensitization of keloid fibroblasts by quercetin through the PI3K/Akt pathway is dependent on regulation of HIF-1α

Keloids are raised, red, hard and irregular tumors that are prone to extend beyond the wound borders. Surgical excision is not sufficient to eradicate a keloid. Adjuvant therapy with radiation is a recommended treatment that reportedly achieves improved efficacy. However, radiation does not only kill cells in the keloid tissue but also stimulates their resistance, and intractable cases can display continuous recurrence. Quercetin was initially extracted from natural products and is used as a dietary supplement. The role of quercetin as an oxidant scavenger has been highlighted in many studies and has drawn interest to the application of ionizing radiation (IR) sensitization. In this study, we first demonstrate that keloid fibroblasts acquire resistance after IR treatment, and this can be relieved by treatment with quercetin. Further, we showed that hypoxia-inducible factor 1 (HIF-1), a prognostic marker used in clinical practice after radiation therapy, was associated with stronger radioresistance in keloid fibroblasts, which was downregulated after quercetin treatment. The inhibition of HIF-1 expression by quercetin was found to be dependent on the phosphatidylinositol-3-kinase (PI3K)/Akt pathway. Quercetin has been reported to reduce the phosphorylation of Akt. Taken together, we revealed one mechanism underlying the suppression of radioresistance by quercetin, which involved the regulation of HIF-1 alpha by the PI3K/Akt pathway. Our study provides a molecular basis for the application of quercetin in radiation sensitization in the treatment of keloids.