15-LOX-1 has diverse roles in the resensitization of resistant cancer cell lines to doxorubicin

Kazan, Hasan Huseyin
Urfali-Mamatoglu, Cagri
Yalcin, Gizem Damla
Bulut, Onur
Sezer, Abdullah
Banerjee, Sreeparna
Gündüz, Ufuk
Lipoxygenases (LOXs) are a family of enzymes that can oxygenate polyunsaturated fatty acids. As a member of the family, 15-lipoxygenase-1 (15-LOX-1) specifically metabolizes arachidonic acid and linoleic acid. 15-LOX-1 can affect physiological and pathophysiological events via regulation of the protein-lipid interactome, alterations in intracellular redox state and production of lipid metabolites that are involved in the induction and resolution of inflammation. Although several studies have shown that 15-LOX-1 has an antitumorigenic role in many different cancer models, including breast cancer, the role of the protein in cancer drug resistance has not been established yet. In this study, we, for the first time, aimed to show the potential role of 15-LOX-1 in acquired doxorubicin (DOX) resistance in MCF7 and HeLa cancer cell lines. Our results show that ALOX15 was transcriptionally downregulated in DOX-resistant cells compared with their drug-sensitive counterparts. Moreover, overexpression of ALOX15 in the drug-resistant cells resulted in resensitization of those cells to DOX in a cell-dependent manner. 15-LOX-1 expression could induce apoptosis by activating PPAR gamma and enhance the accumulation of DOX in drug-resistant MCF7 cells by altering cellular motility properties, and membrane dynamics. However, HeLa DOX cells did not show any of these effects but were susceptible to cell death when treated with 13(S)-HODE. These results underline the role and importance of 15-LOX-1 in cancer drug resistance, and points to novel mechanisms as a therapeutic approach to overcome cancer drug resistance.


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Cimen, I; Astarci, E; Banerjee, Sreeparna (Wiley, 2011-09-01)
15-Lipoxygenase-1 (15-LOX-1) is an enzyme of the inflammatory eicosanoid pathway whose expression is known to be lost in colorectal cancer (CRC). We have previously shown that reintroduction of the gene in CRC cell lines slows proliferation and induces apoptosis (Cimen et al. [2009] Cancer Sci 100: 2283-2291). We have hypothesized that 15-LOX-1 may be anti-tumorigenic by the inhibition of the antiapoptotic inflammatory transcription factor nuclear factor kappa B. We show here that ectopic expression of 15-L...
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AKR1B1 and AKR1B10, members of the aldo-keto reductase family of enzymes that participate in the polyol pathway of aldehyde metabolism, are aberrantly expressed in colon cancer. We previously showed that high expression of AKR1B1 (AKR1B1(HIGH)) was associated with enhanced motility, inflammation and poor clinical outcome in colon cancer patients. Using publicly available datasets and ex vivo gene expression analysis (n = 51, Ankara cohort), we have validated our previous in silico finding that AKR1B1(HIGH) ...
Emerging cellular functions of the lipid metabolizing enzyme 15-Lipoxygenase-1
Colakoglu, Melis; Tuncer, Sinem; Banerjee, Sreeparna (Wiley, 2018-10-01)
The oxygenation of polyunsaturated fatty acids such as arachidonic and linoleic acid through lipoxygenases (LOXs) and cyclooxygenases (COXs) leads to the production of bioactive lipids that are important both in the induction of acute inflammation and its resolution. Amongst the several isoforms of LOX that are expressed in mammals, 15-LOX-1 was shown to be important both in the context of inflammation, being expressed in cells of the immune system, and in epithelial cells where the enzyme has been shown to...
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Short chain fatty acids (SCFAs) are produced by commensal bacteria in the gut and are known to reduce inflammation through transcriptional inhibition of cytokines and inflammatory proteins such as cyclooxygenase-2 (COX-2). Butyrate is a SCFA that was reported to alter the mRNA stability of inflammatory genes by increasiing the expression of the RNA binding protein (RBP) Tristetraprolin (TTP). We have hypothesized that butyrate may regulate gene expression post-transcriptionally through global effects on the...
Effects of the quercetin derivative CHNQ, a potent aldo- keto reductase inhibitor, on akr1b1 silenced HCT-116 colorectal cancer cells
Taşkoparan, Betül; Banerjee, Sreeparna; Department of Biology (2016)
Aldo-keto reductases (AKRs) are NAD(P)H dependent oxidoreductases that are known to be involved in the biosynthesis, metabolism and detoxification of a number of substrates including glucose. These enzymes are therefore implicated in the development of diabetic complications. Additionally, this family of enzymes, particularly AKR1B1, has been shown to be involved in pathology of inflammation- associated diseases such as atherosclerosis, asthma, uveitis, sepsis, arthritis, periodontitis and cancer, including...
Citation Formats
H. H. Kazan et al., “15-LOX-1 has diverse roles in the resensitization of resistant cancer cell lines to doxorubicin,” JOURNAL OF CELLULAR PHYSIOLOGY, pp. 4965–4978, 2020, Accessed: 00, 2020. [Online]. Available: https://hdl.handle.net/11511/30108.