Role of cytochrome P450 2J2 on cell proliferation and resistance to an anticancer agent in hepatocellular carcinoma HepG2 cells

Hwang,Geun  Hye; Park,So  Mi; Han,Ho  Jae; Baek,Kyoung  Min; Kim,Joong  Sun; Chang,Woochul; Lee,Ho  Jin; Yun,Seung  Pil; Ryu,Jung  Min; Lee,Min  Young

doi:10.3892/ol.2017.6846

Role of cytochrome P450 2J2 on cell proliferation and resistance to an anticancer agent in hepatocellular carcinoma HepG2 cells

Authors:
- Geun Hye Hwang
- So Mi Park
- Ho Jae Han
- Kyoung Min Baek
- Joong Sun Kim
- Woochul Chang
- Ho Jin Lee
- Seung Pil Yun
- Jung Min Ryu
- Min Young Lee
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Affiliations: College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 41566, Republic of Korea, College of Veterinary Medicine, Seoul National University, Seoul 08826, Republic of Korea, Department of Cardiovascular and Neurological Diseases, College of Oriental Medicine, Daegu Haany University, Daegu 42158, Republic of Korea, Research Center, Dongnam Institute of Radiological and Medical Sciences, Busan 46033, Republic of Korea, Department of Biology Education, College of Education, Pusan National University, Busan 46241, Republic of Korea, Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA, Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA, College of Veterinary Medicine, Chonnam National University, Gwangju 61186, Republic of Korea
Published online on: August 28, 2017 https://doi.org/10.3892/ol.2017.6846
Pages: 5484-5490

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Abstract

The present study examined the role of human cytochrome P450 2J2 (CYP2J2) on cell proliferation and resistance to an anticancer agent using stable hepatocellular carcinoma HepG2 cells overexpressing CYP2J2. Overexpression of CYP2J2 significantly increased HepG2 cell proliferation and the expression levels of cell cycle regulatory proteins, including cyclin D1, cyclin E, cyclin‑dependent kinase (Cdk)2 and Cdk4. CYP2J2‑overexpressing HepG2 cells exhibited high levels of Akt phosphorylation compared with those observed in wild‑type HepG2 cells. Although Akt phosphorylation in both cell lines was significantly attenuated by LY294002, a specific phosphoinositide 3‑kinase/Akt signaling inhibitor, the levels of Akt phosphorylation following treatment with LY294002 were higher in CYP2J2‑overexpressing HepG2 cells than in wild‑type HepG2 cells. Cell counting revealed that proliferation was reduced by LY294002 in both cell lines; however, CYP2J2‑overexpressing HepG2 cell numbers were higher than those of wild‑type HepG2 cells following treatment with LY294002. These results indicated that increased cell proliferation by CYP2J2 overexpression is mediated by increased Akt activity. It was also demonstrated that doxorubicin, an anticancer agent, reduced cell viability, induced a significant increase in the B‑cell lymphoma (Bcl)‑2 associated X protein (Bax)/Bcl‑2 ratio and decreased pro‑caspase‑3 levels in wild‑type HepG2 cells. However, the doxorubicin‑induced reduction in cell viability was significantly attenuated by enhanced upregulation of CYP2J2 expression. The increase in the Bax/Bcl‑2 ratio and the decrease in pro‑caspase‑3 levels were also recovered by CYP2J2 overexpression. In conclusion, CYP2J2 serves important roles in cancer cell proliferation and resistance to the anticancer agent doxorubicin in HepG2 cells.

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