Silencing of peroxiredoxin 2 suppresses proliferation and Wnt/β-catenin pathway,and induces senescence in hepatocellular carcinoma

Hepatocellular carcinoma(HCC),a common malignancy worldwide,still lacks effective clinical treatment.The study aimed to investigate the oncogenes that affect the progression of HCC and their possible mechanisms.In our study,we initially confirmed a higher level of PRDX2 in the bile of HCC patients compared to those with choledocholithiasis by 2-DE,LC-MS,and ELISA.Subsequently,we demonstrated the high expression of peroxiredoxin 2(PRDX2)in HCC based on the TCGA database and clinical sample analysis.Furthermore,PRDX2 overexpression enhanced the viability of HCC cells.And PRDX2 silencing induced senescence of HCC cells.In vivo,knockdown of PRDX2 significantly reduced the weight of xenograft tumors.PRDX2 also was found to activate the Wnt/β-catenin pathway by inducingβ-catenin nuclear translocation.Consequently,we proved that silencing PRDX2 could inhibit proliferation and Wnt/β-catenin pathway while promoting senescence in HCC cells.

Inhibitory role of peroxiredoxin 2 in LRRK2 kinase activity induced cellular pathogenesis

Parkinson’s disease(PD) is a major neurodegenerative disease. One of the known genetic contributors to PD pathogenesis is leucine-rich repeat kinase 2(LRRK2) whose mutations with elevated kinase activity could lead to both familial and sporadic PD. However, how the pathogenic kinase activity of LRRK2 is regulated remains largely unclear. Here we report that peroxiredoxin 2(Prx2) was identified as a novel interacting protein to LRRK2 with preferential expression in dopaminergic neurons over other Prx proteins. We also confirmed that Prx2 interacted with LRRK2 through its COR domain and its overexpression significantly decreased the kinase activity of mutant LRRK2. Functionally, overexpressed Prx2 rescued the transfected cells from LRRK2 mutant induced apoptotic processes. Importantly, overexpressed Prx2 reversed the altered subcellular distribution of cationindependent mannose 6-phosphate receptor(CI-M6 PR) induced by PD-mutant LRRK2. Our results suggest that,by interacting with LRRK2, Prx2 may play an inhibitory role in the LRRK2 mediated cellular toxicity in PD by inhibiting its kinase activity.

Selective silencing of 2Cys and type-ⅡB Peroxiredoxins discloses their roles in cell redox state and stress signaling

Peroxiredoxins （Prx） catalyse the reduction of hydrogen peroxide （H2O2） and, in association with catalases and other peroxidases, may participate in signal transduction by regulating intercel ular H2O2 concentration that in turn can control gene transcription and cel signaling. Using virus-induced-gene-silencing （VIGS）, 2-Cys Peroxiredoxin （2CysPrx） family and type-II Peroxiredoxin B （PrxI B） gene were silenced in Nicotiana benthamiana, to study the impact that the loss of function of each Prx would have in the antioxidant system under control （22℃） and severe heat stress conditions （48 ℃）. The results showed that both Prxs, although in different organel es, influence the regeneration of ascorbate to a significant extent, but with different purposes. 2CysPrx affects abscisic acid （ABA） biosynthesis through ascorbate, while PrxIIB does it probably;through the xanthophyl cycle. Moreover, 2CysPrx is key in H2O2 scavenging and in consequence in the regulation of ABA signal-ing downstream of reactive oxygen species and PrxIIB provides an important assistance for H2O2 peroxisome scavenges.

Redox-stress response resistance(RRR)mediated by hyperoxidation of peroxiredoxin 2 in senescent cells

Aging is closely related to redox regulation.In our previous work,we proposed a new concept,“redox-stress response capacity(RRC),”and found that the decline in RRC was a dynamic characteristic of aging.However,the mechanism of RRC decline during aging remains unknown.In this study,using the senescent human fibroblast cell model and Caenorhabditis elegans model,we identified that peroxiredoxin 2(PRDX2),as a hydrogen peroxide(H_(2)O_(2))sensor,was involved in mediating RRC.PRDX2 knockdown led to a decline of RRC and accelerated senescence in fibroblasts and prdx-2 mutant C.elegans also showed decreased RRC.The mechanism study showed that the decreased sensor activity of PRDX2 was related to the increase in hyperoxidation of PRDX2 in senescent cells.Moreover,the level of PRDX2 hyperoxidation also increased in old C.elegans.Simultaneous overexpression of both PRDX2 and sulfiredoxin(SRX)rescued the reduced RRC and delayed senescence.The increase in PRDX2 hyperoxidation in senescent cells led to a decrease in its sensor activity,resulting in the decreased cellular response to H_(2)O_(2),which is similar to the mechanism of insulin resistance due to the lower insulin receptor sensitivity.Treatment of young cells with a high level of H_(2)O_(2)to induce a higher level of PRDX2-SO_(3) resulted in mimicking the RRC decline in senescent cells,which is also similar to a model of insulin resistance induced by high levels of insulin.All these results thrillingly indicate that there is an insulin-resistance-like phenomenon in senescent cells,we named it redox-stress response resistance,RRR.RRR in senescent cells is an important new discovery that explains RRC decline during aging and reveals the internal relationship between redox regulation and aging from a new perspective.