Beyond reduction of atherosclerosis: PON2 provides apoptosis resistance and stabilizes tumor cells

Abstract

Major contributors to atherosclerosis are oxidative damage and endoplasmic reticulum (ER) stress-induced apoptosis; both of which can be diminished by the anti-oxidative protein paraoxonase-2 (PON2). ER stress is also relevant to cancer and associated with anti-cancer treatment resistance. Hence, we addressed, for the first time, whether PON2 contributes to tumorigenesis and apoptotic escape. Intriguingly, we found that several human tumors upregulated PON2 and such overexpression provided resistance to different chemotherapeutics (imatinib, doxorubicine, staurosporine, or actinomycin) in cell culture models. This was reversed after PON2 knock-down. Remarkably, just deficiency of PON2 caused apoptosis of selective tumor cells per se, demonstrating a previously unanticipated oncogenic function. We found a dual mechanistic role. During ER stress, high PON2 levels lowered redox-triggered induction of pro-apoptotic CHOP particularly via the JNK pathway, which prevented mitochondrial cell death signaling. Apart from CHOP, PON2 also diminished intrinsic apoptosis as it prevented mitochondrial superoxide formation, cardiolipin peroxidation, cytochrome c release, and caspase activation. Ligand-stimulated apoptosis by TRAIL or TNFα remained unchanged. Finally, PON2 knock-down caused vast reactive oxygen species formation and stimulated JNK-triggered CHOP expression, but inhibition of JNK signaling did not prevent cell death, demonstrating the pleiotropic, dominating anti-oxidative effect of PON2. Therefore, targeting redox balance is powerful to induce selective tumor cell death and proposes PON2 as new putative anti-tumor candidate.

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

“…Approximately 60% confluent cells were transfected with 50 nm PON2-specific or scrambled Stealth small interfering RNA (siRNA) (Invitrogen) using either SaintRed (Synvolux) or Lipofectamine RNAiMax (Invitrogen) transfection reagent according to the supplier's instructions. siRNA sequences and methods have been previously described (32). Stimulation with 3OC12 or LPS (Escherichia coli 0111:B4; Sigma) was performed 2.5 to 3 days after treatment since this was the time point of maximal knockdown.…”

“…The PON2 mutant retains its antioxidant and antiapoptotic functions but does not have 3OC12 hydrolytic activity (32). Thus, this mutant controls for effects due to increased protein expression and any effects of PON2 not associated with its hydrolytic activity.…”

The relation of serum paraoxonase-1 activity with isolated coronary artery ectasia: an observational study

“…PON aynı zamanda serbest radikallerin temizlenmesinde rol oynar ve bu radikallerin hücrenin yapısal komponentleri olan lipitler ve DNA üzerinde bulunan yapısal proteinlere vereceği zararı da azaltabilir (28)(29)(30)(31)(32)(33)(34). Pek çok yönden benzer bir patoloji olan aterosklerozun patogenezinde artan serbest radikallerin LDLK oksidasyonu yanın-da diğer hücresel komponentlere vermiş oldukları zarar da önem-lidir (28,35). Serbest oksijen radikallerinin yapmış olduğu DNA hasarı da ateroskleroz gelişiminde önemlidir (36,37).…”

Estudo das paraoxonases 1, 2 e 3 em pacientes portadores de anemia falciforme"

“…A PON2 é um dos três membros, altamente conservados, da família de enzimas paraoxonase (Witte et al, 2011). Com base em uma análise filogenética, a PON2 é o membro mais antigo, seguido pela PON3 e PON1 (Primo-Parmo et al, 1996;.…”

“…Ainda, com localização primária na membrana plasmática e região perinuclear, a PON2 também encontra-se em organelas celulares tais como, retículo endoplasmático, lisossomos e mitocôndrias (Horke et al, 2008;Rothem et al, 2007;Witte et al, 2011).…”