Crosstalk between osteoprotegerin (OPG), fatty acid synthase (FASN) and, cycloxygenase-2 (COX-2) in breast cancer: implications in carcinogenesis

Abstract

The crosstalk between malignant and nonmalignant cells in the tumor microenvironment, as maneuvered by cytokines/chemokines, drives breast cancer progression. In our previous study, we discovered Osteoprotegerin (OPG) as one of the cytokines heavily secreted by breast cancer cells. We demonstrated that OPG is expressed and secreted at very high levels from the highly invasive breast cancer cell lines SUM149PT and SUM1315MO2 as compared to normal human mammary epithelial HMEC cells. OPG was involved in modulating aneuploidy, cell proliferation, and angiogenesis in breast cancer. Mass spectrometry analysis performed in this study revealed OPG interacts with fatty acid synthase (FASN), which is a key enzyme of the fatty acid biosynthetic pathway in breast cancer cells. Further, electron microscopy, immunofluorescence, and fluorescence quantitation assays highlighted the presence of a large number of lipid bodies (lipid droplets) in SUM149PT and SUM1315MO2 cells in comparison to HMEC. We recently showed upregulation of the COX-2 inflammatory pathway and its metabolite PGE2 secretion in SUM149PT and SUM1315MO2 breast cancer cells. Interestingly, human breast cancer tissue samples displayed high expression of OPG, PGE2 and fatty acid synthase (FASN). FASN is a multifunctional enzyme involved in lipid biosynthesis. Immunofluorescence staining revealed the co-existence of COX-2 and FASN in the lipid bodies of breast cancer cells. We reasoned that there might be crosstalk between OPG, FASN, and COX-2 that sustains the inflammatory pathways in breast cancer. Interestingly, knocking down OPG by CRISPR/Cas9 gene editing in breast cancer cells decreased FASN expression at the protein level. Here, we identified cis-acting elements involved in the transcriptional regulation of COX-2 and FASN by recombinant human OPG (rhOPG). Treatment with FASN inhibitor C75 and COX-2 inhibitor celecoxib individually decreased the number of lipid bodies/cell, downregulated phosphorylation of ERK, GSK3β, and induced apoptosis by caspase-3/7 and caspase-9 activation. But a more efficient and effective decrease in lipid bodies/cell and survival kinase signaling was observed upon combining the drug treatments for the aggressive cancer cells. Collectively, the novel biological crosstalk between OPG, FASN, and COX-2 advocates for combinatorial drug treatment to block these players of carcinogenesis as a promising therapeutic target to treat highly invasive breast cancer.

Osteoprotegerin Disruption Attenuates HySu-Induced Pulmonary Hypertension Through Integrin α v β 3 /FAK/AKT Pathway Suppression

“…32,33 Similarly, we observed upregulated α v β 3 integrin in mPASMCS and PAs, where its interaction with osteoprotegerin induced of FAK and AKT phosphorylation and cell proliferation. Previous studies have also shown that osteoprotegerin secreted by breast cancer cells could interact with fatty acid synthase, 8 which plays a key role in pulmonary vascular remodeling. 34 However, rOPG stimulation induced primary OPG -/-PASMC proliferation independent of fatty acid synthase expression ( Figure VI in the Data Supplement).…”

“…6,7 However, recent clinical and experimental data have also linked osteoprotegerin to carcinogenesis and a range of cardiovascular disorders, including PAH. [8][9][10][11] Notably, clinical data showed that osteoprotegerin serum levels were higher in idiopathic pulmonary hypertension and associated with the indicators of disease severity and prognosis, and also indicated that osteoprotegerin expression was increased in both concentric and plexiform lesions in remodeled pulmonary arteries.…”

“…14,15 These data expand the functional significance of osteoprotegerin beyond its presumed role as a receptor activator of nuclear factor-κB ligand and TRAIL decoy receptor, and suggest that it may interact with integrins or fatty acid synthase. 8,14,15 This is greatly relevant because pulmonary arterial smooth muscle cells (PASMCs) express several integrin molecules that regulate pulmonary vascular remodeling and contribute to PAH progression. 16,17 Integrins are a large family of structurally related heterodimeric transmembrane receptors that regulate cell-cell and cell-matrix contacts.…”

Fatty acid synthase regulates the pathogenicity of Th17 cells

“…Those fatty acids can be further modified and used for cellular processes, such as membrane formation and posttranslational protein modification [7,9,10]. The specific FASN inhibitor C75 is effective in inhibiting tumor growth in numerous cancer models [11][12][13]. Whether FASN is important for Th17 effector function in comparison to other CD4 + Th subsets remains to be determined.…”

Reduction of Inflammatory Response by Way of Oxidative Stress with San Huang Decoction (SHD) In Perioperative Care: A Randomized Clinical Trial

“…It was reported that a high level of the inflammatory cytokine IL-6 has been associated with increased tumor stage, lymph node infiltration, recurrence, and treatment resistance [34]. Several cytokines regulate the inflammatory tumor microenvironment, of which CRP, IL-6, and TNF-α stimulate cancer cell proliferation and invasion [35]. Our results indicate that patients following breast cancer surgery in the 7 days postoperatively experienced elevated serological levels of CRP, IL-6, and TNF-α than before operation.…”