EXPRESSION OF CYTOCHROME P450 2J2 AND CYCLOOXYGENASE-2 IN HUMAN BREAST CANCER CELLS AND STRATEGIES TO MINIMISE ANTI-TUMOUR DRUG RESISTANCE

Abstract

Advanced cancers are often drug resistant and highly metastatic. Understanding the factors and mechanisms that drive metastasis and drug resistance could provide new targets for the development of innovative treatments. Eicosanoids are the products of arachidonic acid biotransformation and have been associated with altered tumourigenesis and anti-cancer drug efficacy. The cyclooxygenase-2 (COX2) and cytochrome P450 (CYP) metabolic pathways produce prostaglandins and epoxyeicosatrienoic acids (EETs) respectively; these genes are often amplified in cancer. Where COX2-derived prostaglandins have been shown to drive the metastatic behaviour of many tumours, the significance of CYP2J2 overexpression is not yet fully established. MDA-MB-468 triple negative breast cancer cells that overexpress COX2 (MDA-COX2) and CYP2J2 (MDA-2J2) were available for the present project. Both cell types proliferated rapidly and overexpress genes linked to drug resistance. Real time polymerase chain reaction and immunoblotting techniques revealed that several drug metabolising enzymes were overexpressed in MDA-2J2 cells. Upregulation of stem cell marker phase 1 enzyme aldehyde dehydrogenase 1A1 (ALDH1A1) mRNA was found at 293-fold of MDA- 468 control. In MDA-2J2; this was also evident at the protein level. The gene expressions of other ALDH groups were not noticeably increased in comparison to MDA-468 control. In contrast, the gene profile expressions in MDA-COX2 cells did not show a significant fold increase of ALDH1A1 expression in comparison to MDA- 468 control. The effect of increased ALDH1A1 could promote the biotransformation of a number of oncology drugs in cancer cells, and lead to drug resistance by decreasing efficacy. In MDA-2J2 cells, overexpression of ALDH1A1 was further associated with activation of the p38 mitogen-activated protein kinase and protein kinase C signaling pathways. These findings may provide a link between the overexpression of CYP2J2 and aggressive and drug-resistant cancer phenotypes, and promote identification of novel targets for the treatment of aggressive or advanced cancers from an increased understanding of the role of CYP2J2 in aggressive or advanced cancers.