Abstract
Ultraviolet (UV) light is a leading cause of diseases, such as skin cancers and cataracts. A main process mediating UV-induced pathogenesis is the production of reactive oxygen species (ROS). Excessive ROS levels induce the formation of DNA adducts (e.g., pyrimidine dimers) and result in stalled DNA replication forks. In addition, ROS promotes phosphorylation of tyrosine kinase-coupled hormone receptors and alters downstream energy metabolism. With respect to the risk of UV-induced photocarcinogenesis and photodamage, the antitumoral and antioxidant functions of natural compounds become important for reducing UV-induced adverse effects. One important question in the field is what determines the differential sensitivity of various types of cells to UV light and how exogenous molecules, such as phytochemicals, protect normal cells from UV-inflicted damage while potentiating tumor cell death, presumably via interaction with intracellular target molecules and signaling pathways. Several endogenous molecules have emerged as possible players mediating UV-triggered DNA damage responses. Specifically, UV activates the PIKK (phosphatidylinositol 3-kinase-related kinase) family members, which include DNA-PKcs, ATM (ataxia telangiectasia mutated) and mTOR (mammalian target of rapamycin), whose signaling can be affected by energy metabolism; however, it remains unclear to what extent the activation of hormone receptors regulates PIKKs and whether this crosstalk occurs in all types of cells in response to UV. This review focuses on proteomic descriptions of the relationships between cellular photosensitivity and the phenotypic expression of the insulin/insulin-like growth receptor. It covers the cAMP-dependent pathways, which have recently been shown to regulate the DNA repair machinery through interactions with the PIKK family members. Finally, this review provides a strategic illustration of how UV-induced mitogenic activity is modulated by the insulin sensitizer, ursolic acid (UA), which results in the metabolic adaptation of normal cells against UV-induced ROS, and the metabolic switch of tumor cells subject to UV-induced damage. The multifaceted natural compound, UA, specifically inhibits photo-oxidative DNA damage in retinal pigment epithelial cells while enhancing that in skin melanoma. Considering the UA-mediated differential effects on cell bioenergetics, this article reviews the disparities in glucose metabolism between tumor and normal cells, along with (peroxisome proliferator-activated receptor-γ coactivator 1α)-dependent mitochondrial metabolism and redox (reduction-oxidation) control to demonstrate UA-induced synthetic lethality in tumor cells.
Highlights
The antitumoral effect of ursolic acid (UA) exerted at high dosages is associated with inactivation of the PI3K-AKT-mTOR-(NF-κB) signaling pathway, which is in turn activated for reducing endoplasmic reticulum stress and restores insulin signaling in mice fed with a high fat diet [35,36]
We have observed oxidative stress in mitochondria increased by UV-VIS radiation, which, was decreased upon rapamycin pretreatment in retinal pigment epithelial cells, implying an intricate interplay between p53 and mTOR signaling in the regulation of mitochondrial metabolism [18]
When cells are exposed to UV, the induced DNA damage and oxidative stress provoke activation of PIKKs, PI3K and MAPK, leading to cell cycle arrest, DNA repair and metabolic adaptation via p53 and NF-κB signaling
Summary
The majority of solar radiation delivered to Earth surface is distributed in the region of near-infrared, accompanied by far ultraviolet (UV) radiation and visible light This broadband radiation, containing only a small fraction of the UV radiation, has the potential to cause skin damage and malignant transformation [1,2,3]. Phosphorylation and promoting Rad trafficking to the site of damaged DNA [13] In photosensitive tissues, such as retinal rod outer segments, intrinsic tyrosine kinases can be activated by light [15]. The 97-kDa protein was found by Ghalayini et al to be phosphorylated in rat retinal rod outer segments in a light-dependent manner [17] This indicates that activation of insulin receptor generally reduces cellular photosensitivity by counteracting UV-induced pro-apoptotic cell signaling [18]. By applying broadband radiation from a mercury arc lamp, the light-induced p53 and NF-κB activation of retinal pigment epithelial (RPE) were both observed to be enhanced by the pretreatment with insulin and the insulin receptor sensitizer, ursolic acid (UA) [18]
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