The role of 15-LOX-1 in resistance to chemotherapeutics

Kazan, Hasan Hüseyin
Chemotherapy is one of the best options to treat cancer. However, drug resistance can limit the efficacy of chemotherapeutics. There have been several reasons for the cancer drug resistance including the export of the drug from cells, inactivation of drugs by enzymatic processes, mutations that limit the binding of the drugs to the target proteins, resistance to cell death mechanism by cellular manipulations and reorganization of the cell membrane. 15-Lipoxygenase-1 (15-LOX-1) is a member of the lipoxygenase family containing iron and catalysing oxygenation of the polyunsaturated fatty acids. Due to this role, 15-LOX-1 is involved in the regulation of critical physiological conditions. However, disruption of the 15-LOX-1-mediated pathway could also trigger pathophysiological conditions, including cancer. There have been numerous reports that combine 15-LOX-1 function and cancer, and 15-LOX-1 is generally regarded as a tumour suppressor protein because of its main product that can activate the apoptosis. Although 15-LOX-1 and cancer relationship has been well defined, the role of 15-LOX-1 in cancer drug resistance has not yet been documented. The present study aims to identify the possible involvement of the 15-LOX-1 protein and its pathways in the cancer drug resistance by focusing particularly on doxorubicin resistance. The results underlined that 15-LOX-1 was downregulated in doxorubicin-resistant cancer cells but the downregulation of 15-LOX-1 was cell and/or drug specific. Moreover, overexpression of 15-LOX-1 in doxorubicin-resistant cancer cells triggered cell death mechanisms in a cell-specific manner and partially re-sensitized the cells towards doxorubicin. Molecular studies revealed that this effect was also cell specific and was a result of cell membrane reorganization in doxorubicin-resistant MCF7 cell line. Still, further molecular and clinical studies are needed to completely explore the role of 15-LOX-1 in cancer drug resistance