New targets for colorectal cancer treatment: CYP2W1

A novel human cytochrome P450, CYP2W1, was first cloned and described a few years ago. This unique CYP is expressed mainly in fetal or neoplastic tissues (especially in colorectal cancer), whereas its expression in healthy adult tissues is rather low. The CYP2W1 protein has several interesting features. Unlike other CYPs, CYP2W1 is oriented towards the lumen of the endoplasmic reticulum which makes it available to its glycosylation machinery and indeed, a portion of the CYP2W1 protein is glycosylated at position Asn177. CYP2W1 protein is present also on the cell surface.

Gene expression of CYP2W1 is epigenetically regulated and the higher expression during fetal period suggests CYP2W1 to be involved in processes needed for cell growth or development. Such a function may be reiterated later in carcinogenesis.

CYP2W1 metabolizes benzphetamine and arachidonic acid and activates several procarcinogens, particularly polycyclic hydrocarbon diols, which may be of significance in carcinogenic processes. Many gene polymorphisms have been identified including several non-synonymous SNPs that may alter the enzyme function. Some have been shown to be associated with the colorectal cancer risk. Immunohistochemically assessed expression of CYP2W1 seems to be an independent prognostic factor in 162 patients with stages II and III colorectal cancer. Overall survival was lower in patients with high expression of CYP2W1 in the tumours.

Taken together, CYP2W1 a promising therapeutical target for colon cancer treatment either by specific antibodies or a prodrug activated by CYP2W1 if a specific substrate / prodrug of CYP2W1 is found. Its expression may serve as a prognostic factor for malignancy and survival in colon cancer.

The work was supported by the Swedish Cancer Foundation, The Swedish Research Council and the OPVK project CZ.1.07/2.3.00/20.0019

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