The expression of CYP2W1 in colorectal primary tumors, corresponding lymph node metastases and liver metastases

Stenstedt, Kristina; Hallström, Marja; Lédel, Frida; Ragnhammar, Peter; Ingelman‐Sundberg, Magnus; Johansson, Inger; Edler, David

doi:10.3109/0284186x.2014.887224

Cited by 17 publications

(15 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…High CYP2W1 levels were observed in approximately 30% of human CRC specimens [ 5 , 6 ]. Recently significant expression has also been seen in liver cancers with even higher expression in liver metastases than in the parent tumor from the same patient [ 7 ]. In both colon and liver cancers the prognosis of survival is worse in patients carrying tumors with higher levels of CYP2W1 expression [ 5 , 6 , 8 ].…”

Section: Introductionmentioning

confidence: 99%

Developmental Regulation and Induction of Cytochrome P450 2W1, an Enzyme Expressed in Colon Tumors

et al. 2015

Self Cite

View full text Add to dashboard Cite

Cytochrome P450 2W1 (CYP2W1) is expressed predominantly in colorectal and also in hepatic tumors, whereas the levels are insignificant in the corresponding normal human adult tissues. CYP2W1 has been proposed as an attractive target for colorectal cancer (CRC) therapy by exploiting its ability to activate duocarmycin prodrugs to cytotoxic metabolites. However, its endogenous function, regulation and developmental pattern of expression remain unexplored. Here we report the CYP2W1 developmental expression in the murine and human gastrointestinal tissues. The gene expression in the colon and small intestine commence at early stages of embryonic life and is completely silenced shortly after the birth. Immunohistochemical analysis of human fetal colon revealed that CYP2W1 expression is restricted to the crypt cells. The silencing of CYP2W1 after birth correlates with the increased methylation of CpG-rich regions in both murine and human CYP2W1 genes. Analysis of CYP2W1 expression in the colon adenocarcinoma cell line HCC2998 revealed that the gene expression can be induced by e.g. the antitumor agent imatinib, linoleic acid and its derivatives. The imatinib mediated induction of CYP2W1 suggests an adjuvant therapy to treatment with duocarmycins that thus would involve induction of tumor CYP2W1 levels followed by the CYP2W1 activated duocarmycin prodrugs. Taken together these data strongly support further exploration of CYP2W1 as a specific drug target in CRC.

show abstract

Section: Introductionmentioning

confidence: 99%

Developmental Regulation and Induction of Cytochrome P450 2W1, an Enzyme Expressed in Colon Tumors

et al. 2015

Self Cite

View full text Add to dashboard Cite

show abstract

“…The presence of CYP2W1 in the surrounding normal tissues was negligible or absent (Edler et al, 2009;Stenstedt et al, 2012). Moreover, a follow-up study demonstrated even higher frequency of CYP2W1 expression (48%) in the liver metastases from the CRC patients (Stenstedt et al, 2014). This indicates a higher expression in more malignant forms of the colon cancer cells.…”

Section: Cyp2w1 As a Prognostic Marker Of Crcmentioning

confidence: 95%

The CYP2W1 enzyme: regulation, properties and activation of prodrugs

Guo

Johansson

Mkrtchian

et al. 2016

Drug Metabolism Reviews

Self Cite

View full text Add to dashboard Cite

CYP2W1 is expressed in the course of development of the gastrointestinal tract, silenced after birth in intestine and colon by epigenetic modifications, but activated following demethylation in colorectal cancer (CRC). The expression levels in CRC positively correlate with the degree of malignancy, are higher in metastases and are predictive of colon cancer survival. The CYP2W1 transcripts have been detected also in hepatocellular carcinoma, adrenocortical carcinoma, childhood rhabdomyosarcoma and breast cancer; however, here the protein expression remains to be confirmed. The CYP2W1 enzyme has an inverted orientation in the endoplasmic reticulum membrane, as compared to other cytochrome P450s and its immediate electron donor is unknown. Several lipid ligands have been proposed as endogenous substrates, among which retinol derivatives appear to have the highest affinities. However, the role of CYP2W1 in the endogenous and tumor localized metabolism of retinol derivatives has yet to be clarified. Indolines constitute high affinity exogenous compounds and specific chloromethylindolines have been shown to be activated by CYP2W1 into cytotoxic products in vitro and also in vivo, inhibiting the growth of human colon tumors in a mouse xenograft model. The CRC specific localization of CYP2W1 and its effective prodrug activation makes it a very promising target for future development of cancer therapeutics.

show abstract

“…Since almost half of CRC metastases express CYP2W1, this enzyme is a possible target for treatment of CRC liver metastasis [6]. We have shown, using both a cell culture model and a mouse xenograft model (CYP2W1-expressing human colon carcinoma cells), that duocarmycin (chloromethylindolines) prodrugs can be converted to cytotoxic products by CYP2W1 [7].…”

Section: Introductionmentioning

confidence: 99%

Human Cytochrome P450 2W1 Is Not Expressed in Adrenal Cortex and Is Only Rarely Expressed in Adrenocortical Carcinomas

et al. 2016

Self Cite

View full text Add to dashboard Cite

Human cytochome P450 2W1 (CYP2W1) enzyme is expressed in fetal colon and in colon tumors. The level of expression is higher in colon metastases than in the parent tumors and the enzyme is a possible drug target for treatment of colorectal cancer, as demonstrated in mouse xenograft studies. A previous study published in this journal reported that CYP2W1 is highly expressed in normal and transformed adrenal tissue. However, adrenal expression of CYP2W1 protein was not seen in previous studies in our research group. To clarify this inconsistency, we have used qRT-PCR and Western blotting with CYP2W1-specific antibodies to probe a panel of 27 adrenocortical carcinomas and 35 normal adrenal cortex samples. CYP2W1 mRNA expression is seen in all samples. However, significant CYP2W1 protein expression was found in only one tumor sample (a testosterone-producing adrenocortical carcinoma) and not in any normal tissue. Differences in the specificity of the CYP2W1 antibodies used in the two studies may explain the apparent discrepancy. We conclude that normal adrenal tissue lacks P450 2W1 enzyme expression; also, adrenocortical carcinomas generally do not express the enzyme. This information thus underline the colon cancer specificity of CYP2W1 enzyme expression and has implications for the development of anti-colon cancer therapies based on CYP2W1 as a drug target, since 2W1-dependent bioactivation of prodrugs for CYP2W1 will not take place in normal adrenal tissue or other non-transformed tissues.

show abstract

The expression of CYP2W1 in colorectal primary tumors, corresponding lymph node metastases and liver metastases

Cited by 17 publications

References 23 publications

Developmental Regulation and Induction of Cytochrome P450 2W1, an Enzyme Expressed in Colon Tumors

Developmental Regulation and Induction of Cytochrome P450 2W1, an Enzyme Expressed in Colon Tumors

The CYP2W1 enzyme: regulation, properties and activation of prodrugs

Human Cytochrome P450 2W1 Is Not Expressed in Adrenal Cortex and Is Only Rarely Expressed in Adrenocortical Carcinomas

Contact Info

Product

Resources

About