Ursolic acid-regulated energy metabolism-reliever or propeller of ultraviolet-induced oxidative stress and DNA damage?

Yuan Hao Lee, Youping Sun, Randolph D Glickman

Research output: Contribution to journalReview article

2 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)399-425
Number of pages27
JournalProteomes
Volume2
Issue number3
DOIs
StatePublished - Sep 1 2014

Fingerprint

Oxidative stress
Propellers
Energy Metabolism
DNA Damage
Oxidative Stress
Tumors
Reactive Oxygen Species
Phosphatidylinositol 3-Kinase
DNA
Insulin
Metabolism
Molecules
Skin
Phosphotransferases
Cells
Hormones
Pyrimidine Dimers
Ultraviolet Rays
Peroxisome Proliferator-Activated Receptors
Phosphorylation

Keywords

  • Hormone receptors
  • Phosphatidylinositol 3-kinase-related kinases
  • Ultraviolet
  • Ursolic acid

ASJC Scopus subject areas

  • Structural Biology
  • Biochemistry
  • Molecular Biology
  • Clinical Biochemistry

Cite this

Ursolic acid-regulated energy metabolism-reliever or propeller of ultraviolet-induced oxidative stress and DNA damage? / Lee, Yuan Hao; Sun, Youping; Glickman, Randolph D.

In: Proteomes, Vol. 2, No. 3, 01.09.2014, p. 399-425.

Research output: Contribution to journalReview article

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