title: Emodin attenuates radioresistance induced by hypoxia in HepG2 cells via the enhancement of PARP1 cleavage and inhibition of JMJD2B.
abstract: Radioresistance in the tumor and radiotoxicity in the non‑tumorous liver significantly restrict efficient radiotherapy of hepatocellular carcinoma (HCC). It is therefore important to study the radioresistance mechanism and development of radiosensitization to optimize the effect of irradiation on cancer cells. Emodin (1, 3, 8‑trihydroxy‑6‑methylanthraquinone) is a plant‑derived polyphenol, possessing anticancer properties. It is known to act as a radiosensitizer in human HCC cell lines. The aim of this study was to evaluate the role of emodin in radioresistance of human HCC cell lines as well as the underlying radiosensitization mechanism. The human HCC cell line (HepG2) was used in this study. Four different treatment groups, i.e., no treatment (control), irradiation (10 Gy, one fraction), emodin (10 µM), and a combination of irradiation and emodin (10 Gy+10 µM) were used for two environmental conditions: hypoxia (1% O2) and normoxia (20% O2). The cells were exposed to the respective treatments for 24 and 72 h. Following the treatment, the cell viability was determined by the 3‑(4,5‑dimethylthiazol‑2‑yl)‑2,5‑diphenyltetrazolium bromide (MTT) assay, and the radiosensitization mechanism was evaluated by western blotting. The proliferation of HepG2 cells was significantly suppressed in the treatment groups under hypoxic and normoxic conditions in the following order: combination of irradiation and emodin>irradiation only >emodin only. The combination of irradiation and emodin induced apoptotic signaling activities such as cleavage of poly (ADP‑ribose) polymerase (PARP)‑1 as well as the downregulation of epigenetic signaling such as JMJD1A and JMJD2B. Emodin attenuated radioresistance in the HepG2 cells via upregulation of the apoptotic signals and down-regulation of the proliferative signals. These results suggested that emodin is a potential candidate for the radiosensitization of HCC cells and can aid in identifying novel therapeutic strategies for HCC radiotherapy.
authors.affiliation: Department of Internal Medicine, Dongnam Institute of Radiological and Medical Sciences, Busan, Republic of Korea.
authors.forename: Sang Youn
authors.initials: SY
authors.lastname: Hwang
authors.affiliation: Department of Research Center, Dongnam Institute of Radiological and Medical Sciences, Busan, Republic of Korea.
authors.forename: Kyu
authors.initials: K
authors.lastname: Heo
authors.affiliation: Department of Internal Medicine, Dongnam Institute of Radiological and Medical Sciences, Busan, Republic of Korea.
authors.forename: Joon Seok
authors.initials: JS
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine, Dongnam Institute of Radiological and Medical Sciences, Busan, Republic of Korea.
authors.forename: Jung Woo
authors.initials: JW
authors.lastname: Im
authors.affiliation: Department of Internal Medicine, Dongnam Institute of Radiological and Medical Sciences, Busan, Republic of Korea.
authors.forename: Sun Mi
authors.initials: SM
authors.lastname: Lee
authors.affiliation: Department of Internal Medicine, Pusan National University College of Medicine, Busan, Republic of Korea.
authors.forename: Mong
authors.initials: M
authors.lastname: Cho
authors.affiliation: Department of Internal Medicine, Pusan National University College of Medicine, Busan, Republic of Korea.
authors.forename: Dae Hwan
authors.initials: DH
authors.lastname: Kang
authors.affiliation: Department of Internal Medicine, Pusan National University College of Medicine, Busan, Republic of Korea.
authors.forename: Jeong
authors.initials: J
authors.lastname: Heo
authors.affiliation: Department of Radiology, Pusan National University College of Medicine, Busan, Republic of Korea.
authors.forename: Jun Woo
authors.initials: JW
authors.lastname: Lee
authors.affiliation: Department of Radiation Oncology, Dongnam Institute of Radiological and Medical Sciences, Busan, Republic of Korea.
authors.forename: Cheol Won
authors.initials: CW
authors.lastname: Choi
authors.affiliation: Department of Radiation Oncology, Dongnam Institute of Radiological and Medical Sciences, Busan, Republic of Korea.
authors.forename: Kwangmo
authors.initials: K
authors.lastname: Yang
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D002453:Cell Cycle / Q000187:drug effects / Q000528:radiation effects; D002455:Cell Division / Q000187:drug effects / Q000528:radiation effects; D015687:Cell Hypoxia / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D004642:Emodin / Q000494:pharmacology*; D005720:Gamma Rays; D015972:Gene Expression Regulation, Neoplastic; D056945:Hep G2 Cells / Q000187:drug effects* / Q000528:radiation effects; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D011836:Radiation Tolerance / Q000187:drug effects*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D013997:Time Factors
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D009363:Neoplasm Proteins; D011838:Radiation-Sensitizing Agents; D056484:Jumonji Domain-Containing Histone Demethylases; C530247:KDM3A protein, human; C523637:KDM4B protein, human; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D004642:Emodin