Radiation Sensitization of Keloid Firboblasts by Quercetin through PI3K/Akt Pathway Dependent Regulation of HIF-1α

Abstract

Objective: Keloid is a benign tumor in the derma, which is generally treated by surgical excision and radiation in clinic. However, recurrence has been an intricate problem in treatment of keloid. Therefore, it is imperative to develop novel interfering means to increase the sensitivity of keloid to radiation. Quercetin is a natural compound, which has been shown to sensitize some tumors to radiation. We tested the potential of quercetin in sensitizing keloid fibroblast to radiation and identified its downstream pathways. Methods: Keloid fibroblast cells were challenged by radiation with or without the presence of quercetin. Cellular response was detected by flow cytometry, western blot, qRT-PCR and immunofluorescence staining. HIF-1α was down-regulated by siRNA transfection. Results: In this study, we firstly demonstrate that keloid fibroblasts acquire resistance after IR treatment, and this can be relieved by treating 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 fibroblast, which was downregulated after quercetin treatment. The inhibition on HIF-1 expression by quercetin was found to depend on phosphatidylinositol-3-kinase (PI3K)/Akt pathway and quercetin also reduce phosphorylation of Akt. Conclusion: Taken together, we revealed a mechanism underlying the suppression on radioresistance by quercetin, which involves the regulation of HIF-1α by PI3K/Akt pathway. Our study provides molecular interpretation for the application quercetin in sensitizing radiation in keloid treatment.

Identification of the active compounds and pharmacological mechanisms of Xiaoqinglong decoction for asthma based on network pharmacology and molecular docking technology

“…Activation of HIF-1a during in ammation can enhance the expression of VEGF and promote airway angiogenesis in patients with asthma [46]. Quercetin can down-regulates the activity of PI3K-Akt signaling pathway to inhibit the expression of HIF-1, which moderates antigen-induced airway in ammation and hyperresponsiveness by regulating VEGF-mediated vascular leakage [47,48]. Regulatory T (Treg) cells play an important role in inhibiting airway in ammation and airway hyperresponsiveness [49].…”

Network Pharmacology Interpretation of Fuzheng–Jiedu Decoction against Colorectal Cancer

“…Besides, a combination of kaempferol and 5-fluorouracil induces apoptosis through PI3K/Akt signaling pathway [61]. Studies show that quercetin-induced apoptosis inhibits PI3K/Akt and apoptosis inhibitor Bcl-2, and the accumulation of HIF-1α also has an inhibitory effect [62]. Diosgenin (Table 1) can upregulate p38 MAPK pathway-related proteins, thus promoting TRAIL (a member of the TNF cytokine family) induced apoptosis [63].…”

Quercetin A potential treatment for keloids

“…Keloids are exuberant overgrowths of scar with excessive fibroblast proliferation and matrix deposition, which has the ability to spread beyond the original boundary of the wound 3. Despite existence of a wide array of therapies available for keloids, no treatment is yet considered completely effective.…”

“…Other promising approaches such as mesenchymal stem cell therapy, fat grafting, electrical stimulation, and deployment of RNA interference seem to be beneficial for the treatment of keloids 5. Over the past years, studies found compelling evidence that indicate the advantageous properties of quercetin as a potential candidate for adjuvant therapy of keloids 3,4…”

“…According to Si et al .’s recent study, keloid fibroblasts treated with quercetin showed augmented sensitisation to radiation compared to untreated cells 3. The main mechanism underlying the suppression of radio-resistance by quercetin is down-regulation of hypoxia-inducible factor 1, a prognostic factor used in clinical practice after radiation therapy, through the phosphoinositide 3-kinase/Akt pathway 3. An in vitro study by Mathangi Ramakrishnan et al .…”