Insulin-Like Growth Factor-1–Mediated DNA Repair in Irradiated Salivary Glands Is Sirtuin-1 Dependent

Abstract

Ionizing radiation is one of the most common cancer treatments; however, the treatment leads to a wide range of debilitating side effects. In patients with head and neck cancer (HNC), the surrounding normal salivary gland is extremely sensitive to therapeutic radiation, and damage to this tissue results in various oral complications and decreased quality of life (QOL). In the current study, mice treated with targeted head and neck radiation showed a significant increase in double-stranded breaks (DSB) in the DNA of parotid salivary gland cells immediately after treatment, and this remained elevated 3 h posttreatment. In contrast, mice pretreated with insulinlike growth factor-1 (IGF-1) showed resolution of the same amount of initial DNA damage by 3 h posttreatment. At acute time points (30 min to 2 h), irradiated parotid glands had significantly decreased levels of the histone deactylase Sirtuin-1 (SirT-1) which has been previously shown to function in DNA repair. Pretreatment with IGF-1 increased SirT-1 protein levels and increased deacetylation of SirT-1 targets involved in DNA repair. Pharmacological inhibition of SirT-1 activity decreased the IGF-1-mediated resolution of DSB. These data suggest that IGF-1 promotes DNA repair in irradiated parotid glands through the maintenance and activation of SirT-1.

Hypoxia-Activated Adipose Mesenchymal Stem Cells Prevents Irradiation-Induced Salivary Hypofunction by Enhanced Paracrine Effect Through Fibroblast Growth Factor 10

“…Although FGF10 contributes to amelioration of IR‐induced salivary damage and AdMSCs exert their therapeutic efficacy against IR‐induced damage through paracrine secretion of trophic mediators, it should be noted that MSC activity may be mediated by the synergism of several of these mediators . Recently, IGF1, GDNF, and FGF7 have been reported as potential therapeutic factors which may contribute to repair of DNA damage, proliferation of salivary gland stem cells, or radioprotection of salivary cells after IR . Furthermore, extracellular vesicles (EV), including exosomes and microvesicles, have been implicated as important mediators of the efficacy in stem cell‐based therapy .…”

“…Since the radioprotective effects of MSC‐derived EVs have not yet been addressed in IR‐induced salivary gland damage, further comparative studies are still required. In addition, stem cell‐based therapy should be tailored in personalized treatment planning because MSCs or MSC‐derived factors may not be efficacious in an inability of the cells to activate appropriate repair response or in the area of depletion of tissue‐specific stem cells due to high‐dosage IR .…”

Radiation-Induced Salivary Gland Dysfunction: Mechanisms, Therapeutics and Future Directions

“…Administration of IR to salivary glands activates an array of signaling pathways that influence the development of acute hyposalivation. Within minutes of IR exposure, DNA double-strand breaks were detected in mouse parotid glands using a neutral comet assay and were associated with increased phosphorylation of the H2A histone family member X (referred to as γH2AX) [59]. Timeline of Radiation-Induced Changes in the Rodent Salivary Gland.…”

Secretome Analysis of Inductive Signals for BM-MSC Transdifferentiation into Salivary Gland Progenitors

“…The pathway encompasses five of our ten putative proteins, CYR61, IGFBP7, FN1, FSTL1, and LAMB2. The IGF pathway plays a critical role in cellular growth and development [85]. Its activation has shown to induce the process of salivary cell differentiation and branching morphogenesis [86].…”