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

Abstract

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.

The Identification of Core Gene Expression Signature in Hepatocellular Carcinoma

“…In HCC patients, the levels of some Cytochrome P450 also changed with the progression of HCC. For instance, CYP2J2, a member in Cytochrome P450 family, was discovered to have critical roles in the proliferation and resistance to the anticancer drug (doxorubicin) in HepG2 cells by decreasing the ratio of Bax/Bcl622 ratio and elevating pro62caspase623 levels [ 44 ]. Genetic polymorphisms of some Cytochrome P450 enzymes, such as CYP2D6 ∗ 10, have been proven to have influence on enzyme activity.…”

Comprehensive Analysis of the Expression and Prognosis of 12 Cytochrome P450s in Human Hepatocellular Carcinoma from the Perspective of Network Pharmacology

“…Downregulated CYP2E1 is regarded as a candidate prognostic biomarker in HCC [51]. Few reports are available concerning CYP2J2 expression in patients with HCC; CYP2J2 overexpression remarkably promotes the proliferation of HepG2 cells and affects the resistance to antitumor agents [52]. In the present study, the expression levels of CYP2E1 and CYP2J2 were low in patients with HCC, and their mRNA expression levels were negatively correlated with tumor grades and stages.…”

Repurposing old drugs in oncology: Opportunities with clinical and regulatory challenges ahead

“…CYP2J2 is involved in the metabolism of astemizole and ebastine but not of loratadine. Overexpression of CYP2J2 has been implicated in the pathogenesis of human cancers and resistance to chemotherapy and is believed to be a potential target to reduce cancer cell proliferation and resistance to chemotherapy . For example, tanshinone IIA dose‐dependently and noncompetitively inhibits CYP2J2‐mediated astemizole O‐demethylation activity, and it significantly decreased viability of human hepatoma HepG2 cells and SiHa cervical cancer cells .…”

“…Overexpression of CYP2J2 has been implicated in the pathogenesis of human cancers and resistance to chemotherapy and is believed to be a potential target to reduce cancer cell proliferation and resistance to chemotherapy. [216][217][218] For example, tanshinone IIA dosedependently and noncompetitively inhibits CYP2J2-mediated astemizole O-demethylation activity, and it significantly decreased viability of human hepatoma HepG2 cells and SiHa cervical cancer cells. 217 Tanshinone IIA-induced apoptotic cell death rate was also significantly attenuated by enhanced upregulation of CYP2J2 expression.…”