Esophageal cancer proliferation is mediated by cytochrome P450 2C9 (CYP2C9)

Cytochrome P450 epoxygenases (CYP450) have been recently shown to promote malignant progression. Here we investigated the mRNA and protein expression and potential clinical relevance of CYP2C9 in esophageal cancer. Highest expression was detected in esophageal adenocarcinoma (EAC; n = 78) and adjacent esophageal mucosa (NEM; n = 79). Levels of CYP2C9 in EAC and NEM were significantly higher compared to esophageal squamous cell carcinoma (ESCC; n = 105). Early tumor stages and well-differentiated tumors showed a significantly higher CYP2C9 expression compared to progressed tumors. Moreover, CYP2C9 expression was correlated to high Ki-67 labeling indices in EAC and Ki-67 positive tumor cells in EAC and ESCC. Selective inhibition of CYP2C9 decreased tumor cell proliferation (KYSE30, PT1590 and OE19) in vitro, which was abolished by 11,12-epoxyeicosatrienoic acid (11,12-EET). Cell-cycle analysis using FACS revealed that inhibition of CYP2C9 leads to a G0/G1 phase cell-cycle arrest. CYP2C9 seems to be relevant for early esophageal cancer development by promoting tumor cell proliferation. Pharmacological inhibition of CYP2C9 might contribute to a more efficient therapy in CYP2C9 highly expressing esophageal cancers.

Research highlights▶ CYP2C9 is significantly higher expressed in EAC compared to ESCC. ▶ CYP2C9 is correlated and morphologically associated to proliferative cells in EAC. ▶ CYP2C9 mediates proliferative effects on tumor cells by cell cycle deregulation. ▶ Pharmacological inhibition of CYP2C9 decreases tumor cell proliferation. ▶ Administration of 11,12-EET abolishes antiproliferative effects of CYP2C9 inhibition.