Colorectal cancer specific cytochrome P450 2W1 (CYP2W1): intracellular localization, glycosylation, and catalytic activity
Abstract
Cytochrome P450 2W1 (CYP2W1) is expressed at high levels in colorectal cancer cells. We have shown previously that a higher tumor expression is associated with less survival.
In this study, we characterize post-translational modification, inverted endoplasmic reticulum (ER) topology, and catalytic activity of CYP2W1. Immunofluorescence microscopy and cell surface biotinylation experiments revealed approx. 8% of the CYP2W1 on the cell surface.
Despite the reverse orientation of CYP2W1 in the ER membrane, apparently making interactions with NADPH-cytochrome P450 reductase impossible, CYP2W1 in HEK293 cells was active in the metabolism of indoline substrates and in activation of aflatoxin B1 into cytotoxic products. The study identifies for the first time a cytochrome P450 with a luminal ER orientation and still retaining catalytic activity.
The results suggest a possibility of using CYP2W1 as a drug target in the treatment of colon cancer using antibodies and/or specific CYP2W1 activated prodrugs.