Proteomics-Metabolomics Combined Approach Identifies Peroxidasin as a Protector against Metabolic and Oxidative Stress in Prostate Cancer

Abstract

: Peroxidasin (PXDN), a human homolog of Drosophila PXDN, belongs to the family of heme peroxidases and has been found to promote oxidative stress in cardiovascular tissue, however, its role in prostate cancer has not been previously elucidated. We hypothesized that PXDN promotes prostate cancer progression via regulation of metabolic and oxidative stress pathways. We analyzed PXDN expression in prostate tissue by immunohistochemistry and found increased PXDN expression with prostate cancer progression as compared to normal tissue or cells. PXDN knockdown followed by proteomic analysis revealed an increase in oxidative stress, mitochondrial dysfunction and gluconeogenesis pathways. Additionally, Liquid Chromatography with tandem mass spectrometry (LC-MS/MS)-based metabolomics confirmed that PXDN knockdown induced global reprogramming associated with increased oxidative stress and decreased nucleotide biosynthesis. We further demonstrated that PXDN knockdown led to an increase in reactive oxygen species (ROS) associated with decreased cell viability and increased apoptosis. Finally, PXDN knockdown decreased colony formation on soft agar. Overall, the data suggest that PXDN promotes progression of prostate cancer by regulating the metabolome, more specifically, by inhibiting oxidative stress leading to decreased apoptosis. Therefore, PXDN may be a biomarker associated with prostate cancer and a potential therapeutic target.

Peroxidan Plays a Tumor-Promoting Role in Oral Squamous Cell Carcinoma

“…The results of this study are consistent with a previous report that PXDN is involved in the Warburg-like effect [ 6 ]. The Warburg effect on cancer cells is believed to promote cancer invasion and metastasis and is one of the 10 hallmarks of cancer [ 13 , 18 , 22 ].…”

“…PXDN is a cell-surface peroxidase associated with the ECM [ 6 ]. In cancer cells, interaction between PXDN and HO-1 promotes invasion by attenuating expression of the ECM proteins fibronectin and laminin [ 12 ].…”

“…Among the overexpressed candidate genes is the extracellular matrix (ECM) protein peroxidasin (PXDN). This protein belongs to a family of heme-containing peroxidases that catalyze the production of reactive oxygen species (ROS), including hydrogen peroxide [ 5 , 6 ]. Overexpression of PXDN is found in malignant glioma [ 7 ], metastatic melanoma [ 8 ], esophageal cancer [ 9 ], and bladder cancer [ 10 ].…”

“…Under aerobic conditions, normal cells produce ATP from glucose-derived pyruvate by mitochondrial oxidative phosphorylation, while the primary source of ATP in cancer cells is aerobic glycolysis [ 14 ]. A recent report suggests that PXDN promotes prostate cancer cell tumorigenicity and viability by eliminating ROS to suppress oxidative stress and apoptosis via the Warburg effect [ 6 ]. Pyruvate kinase (PK), a glycolytic enzyme that catalyzes the last step in glycolysis, is present in mammals in four PK isoforms: PKL, PKR, PKM1, and PKM2.…”

Impregnation of Curcumin into a Biodegradable (Poly-lactic-co-glycolic acid, PLGA) Support, to Transfer Its Well Known In Vitro Effect to an In Vivo Prostate Cancer Model

“…Whereas low levels of intracellular ROS are critical for proper cellular signaling and homeostatic redox balance, high levels are deleterious and can lead to significant reductions in antioxidant defense mechanisms, which results in DNA, protein, and lipid damage [5,6,7]. Oxidative stress contributes to the initiation and progression of PCa by modulating transcription factors, cell cycle regulators, and DNA [5,8,9]. Against this background, several antioxidant-related phytochemicals have been tested for the prevention/treatment of PCa by ameliorating oxidative stress [10,11,12,13], and some have the added advantage of low toxicity [14].…”