Serum 5-LOX: a progressive protein marker for breast cancer and new approach for therapeutic target

Abstract

Lipoxygenase (LOX) pathway has emerged to have a role in carcinogenesis. There is an evidence that both 12-LOX and 5-LOX have procarcinogenic role. We have previously reported the elevated level of serum 12-LOX in breast cancer patients. This study evaluated the serum level of 5-LOX in breast cancer patients and its in vitro inhibition assessment with peptide inhibitor YWCS. The level of 5-LOX was determined by surface plasmon resonance (SPR). The peptide inhibitor of 5-LOX was designed by molecular modeling and kinetic assay was performed by spectrophotometry. The siRNA mediated 5-LOX gene silencing was performed to investigate the effect on proliferation of MDA-MB-231, breast cancer cell line. The serum 5-LOX level in breast cancer (5.69 ± 1.97 ng/µl) was almost 2-fold elevated compared to control (3.53 ± 1.0 ng/µl) (P < 0.0001). The peptide YWCS had shown competitive inhibitory effects with IC50, 2.2 µM and dissociation constant (K D ), 4.92 × 10 -8 M. The siRNA mediated knockdown of 5-LOX, resulted in the decreased gene expression for 5-LOX and increased cell death in MDA-MB-231 cell line and thereby play a key role in reducing tumor proliferation. Thus, it can be concluded that 5-LOX is one of the potential serum protein marker for breast cancer and a promising therapeutic target for the same.

Aberrant ALOX5 Activation Correlates with HER2 Status and Mediates Breast Cancer Biological Activities through Multiple Mechanisms

“…However, the role of ALOX in breast cancer remains much unknown. This study firstly demonstrated that the ALOX5 expression elevated breast cancer tissues compared to control (Figures 1(a) and 1(b) ), which is supported by the report that the mean concentration of serum ALOX5 is significantly higher in breast cancer patients than similar age as the control group [ 17 ]. In addition, the serum level of ALOX5 among individual breast cancer patients displays the same trend as what we observed in breast cancer tissues; only some but not all breast cancer samples screened with the aberrant ALOX5 expression.…”

“…Consistently, ALOX5AP which is necessary for the ALOX5 activation via facilitating the docking of AA to ALOX5 has been found to be overexpressed in breast cancer, particularly in aggressive tumors [ 18 ]. In addition, both ALOX5 and ALOX5AP have prognostic and survival significance in breast cancer patients [ 17 , 18 ], suggesting that the elevated level of the expression is functional. This is supported by our observation that the 5-HETE level was significantly increased in breast cancer tissues ( Figure 1(c) ).…”

“…Rahul et al found that HER2, PR ,and ER status and other clinical histopathological features did not affect the serum level of ALOX5 [ 17 ]. Our findings identified the variation in the tissue ALOX5 level with HER2 status but not RP or ER status ( Figure 1 and Supplementary Table 1 ) and suggested that the expression is likely to be associated with the HER2 overexpression.…”

“…Studies reveal that ALOX5 and its metabolites 5-HETE are overexpressed in cancers and confer growth advantage [ 15 , 16 ]. Rahul et al's work suggests that serum ALOX5 can serve as a progressive protein marker for breast cancer [ 17 ]. Similarly, the aberrant expression of the 5-lipoxygenase-activating protein (5-LOXAP) which activates ALOX5 has prognostic and survival significance in patients with breast cancer [ 18 ].…”

α-Conotoxins Enhance both the In Vivo Suppression of Ehrlich carcinoma Growth and In Vitro Reduction in Cell Viability Elicited by Cyclooxygenase and Lipoxygenase Inhibitors

“…LOXs and the products of their catalytic activity also have an antiapoptotic effect and promote tumor growth. LOX inhibitors and, to a greater extent, drugs that inhibit the activity of both COX and LOX, have an antitumor effect [20,21]. Baicalein, NDGA and zileuton, the drugs of natural origin used in this work, possess the capacity to inhibit lipoxygenase pathways, which results in their antitumor activity.…”