PON3 is upregulated in cancer tissues and protects against mitochondrial superoxide-mediated cell death

Abstract

To achieve malignancy, cancer cells convert numerous signaling pathways, with evasion from cell death being a characteristic hallmark. The cell death machinery represents an anti-cancer target demanding constant identification of tumor-specific signaling molecules. Control of mitochondrial radical formation, particularly superoxide interconnects cell death signals with appropriate mechanistic execution. Superoxide is potentially damaging, but also triggers mitochondrial cytochrome c release. While paraoxonase (PON) enzymes are known to protect against cardiovascular diseases, recent data revealed that PON2 attenuated mitochondrial radical formation and execution of cell death. Another family member, PON3, is poorly investigated. Using various cell culture systems and knockout mice, here we addressed its potential role in cancer. PON3 is found overexpressed in various human tumors and diminishes mitochondrial superoxide formation. It directly interacts with coenzyme Q10 and presumably acts by sequestering ubisemiquinone, leading to enhanced cell death resistance. Localized to the endoplasmic reticulum (ER) and mitochondria, PON3 abrogates apoptosis in response to DNA damage or intrinsic but not extrinsic stimulation. Moreover, PON3 impaired ER stress-induced apoptotic MAPK signaling and CHOP induction. Therefore, our study reveals the mechanism underlying PON3's anti-oxidative effect and demonstrates a previously unanticipated function in tumor cell development. We suggest PONs represent a novel class of enzymes crucially controlling mitochondrial radical generation and cell death. Cancer is one of the most life-threatening diseases and will remain a demanding issue in healthcare given the increase in life expectancy, constantly growing population and incidence of risk-factor acquiring patients. It is well established that several cellular deregulations are required for durable malignant transformation. Among them are sustained proliferation, replicative immortality, evasion of immune destruction and escape from cell death.1 Thus, tumor cells represent complex, broadly re-organized entities such that effective therapies demand tumor-specific identification of underlying mechanisms to reveal 'weak points'. Combinations of multiple targeting strategies with moderate compound concentrations are more promising and provoke less side-effects than highdose single treatment. Moreover, besides targeting the machinery directly involved in cell death execution, the preceding signaling pathways are attractive targets as these harbor critical upstream mediators with many of them understudied. Generally, redox signaling at the mitochondria is a vital pathway relevant to this concept in cancer research, as it controls both energy metabolism and regulation of cell death. Therefore, it is not surprising that mitochondrial dysfunction relates to a plethora of diseases and that many lead compounds are currently being developed in order to manipulate this organelle.2 Importantly, via generation of reactive oxygen species (ROS) or Ca...

Paraoxonase 2 Serves a Proapopotic Function in Mouse and Human Cells in Response to the Pseudomonas aeruginosa Quorum-sensing Molecule N-(3-Oxododecanoyl)-homoserine Lactone

“…DKO R MEF expressed a large number of genes that were cancer-or growth-related, including both PON2 and PON3 (32,37,38). PON2 is overexpressed in a number of cancers, including leukemia, hepatocellular, and prostate (33)(34)(35)(36).…”

Novel Paraoxonase 2-Dependent Mechanism Mediating the Biological Effects of the Pseudomonas aeruginosa Quorum-Sensing Molecule N -(3-Oxo-Dodecanoyl)- l -Homoserine Lactone

“…Generation and culturing of stable EA.hy 926 (EA.hy) cells overexpressing PON2 (EA.hy PON2) and the inactive PON2-H114Q mutant (EA.hy H114Q) and PON2-overexpressing HEK cells have been described previously (22,28). Primary human bronchial epithelial cells (HBEC), human umbilical vein endothelial cells (HUVEC), and primary cell media and supplement mixes were from PromoCell, and cells were cultured as recommended by the supplier.…”

936 Quantitative genome-wide methylation analysis of high-grade non-muscle invasive bladder cancer

“…20,21,43 Indeed, for two of these genes, PON3 and STAT5a, previous studies in mice and cell-line models have described potential tumor suppressor roles. 60,61 If this is the case, then these genes may represent important targets for further studies of functional the significance of methylation and reduced expression in a bladder tumor context, including in vitro investigations of demethylating agents designed to restore gene expression.…”