The synergistic effects of PRDX5 and Nrf2 on lung cancer progression and drug resistance under oxidative stress in the zebrafish models

Previous studies have shown that PRDX5 and Nrf2 are antioxidant proteins related to abnormal reactive oxidative species(ROS).PRDX5 and Nrf2 play a critical role in the progression of inflammations and tumors.The combination of PRDX5 and Nrf2 was examined by Co-immunoprecipitation,western blotting and Immunohistochemistry.H2O2 was applied to affect the production of ROS and induced multi-resistant protein 1(MRP1)expression in NSCLC cells.The zebrafish models mainly investigated the synergistic effects of PRDX5 and Nrf2 on lung cancer drug resistance under oxidative stress.We showed that PRDX5 and Nrf2 form a complex and significantly increase the NSCLC tissues compared to adjacent tissues.The oxidative stress improved the combination of PRDX5 and Nrf2.We demonstrated that the synergy between PRDX5 and Nrf2 is positively related to the proliferation and drug resistance of NSCLC cells in the zebrafish models.In conclusion,our data indicated that PRDX5 could bind to Nrf2 and has a synergistic effect with Nrf2.Meanwhile,in the zebrafish models,PRDX5 and Nrf2 have significant regulatory impacts on lung cancer progression and drug resistance activities under oxidative stress.

Glutathione depletion based Pt(Ⅳ) hybrid mesoporous organosilica delivery system to conquer cisplatin chemoresistance: A “one stone three birds” strategy

The occurrence of acquired resistance to cisplatin(DDP)that induces the toxic drug effects has always been a huge challenge and urgently needs to be resolved in the cancer treatment.The combination of anticancer drugs with different mechanisms can remarkably improve the chemotherapeutic efficiency.Given that glutathione(GSH)plays as the driving factors in the resistance of DDP,here we have firstly proposed a“three birds,one stone”based nanoplatform to achieve triple synergetic effects simultaneously addressing DDP resistance in non-small cell lung cancer(NSCLC).Specifically,we initially designed and synthesized a DDP prodrug[Pt(Ⅳ)]bridged silsesquioxane precursor(Pt-Si).Then Pt-Si and bis[3-(triethoxysilyl)propyl]diselenide(BTESe PD)were integrated into the framework of mesoporous organosilica nanoparticles(MONs)to obtain a nanocarrier MONPt/Se.After loading with norcantharidin(NCTD)and modifying with the aptamer AS1411 based G-quadruplex(Apt),the Apt@NCTD@MONPt/Seexhibit impressive tumor homing capability.Once being endocytosed,(Ⅰ)the diselenide and-O-Pt(Ⅳ)-O-rich scaffold can be reduced by the excessive GSH,followed by(Ⅱ)breaking the redox homeostasis via GSH depletion and precise release of the DDP.Next,the encapsulated NCTD is also released along with the degradation of the nanocarriers thereby(Ⅲ)achieving the GSH depletion and synergistic anti-tumor effect of NCTD and DDP.Taken together,we believe this“one stone,three birds”strategy may be a promising paradigm to conquer drug resistance for clinical care.

Meiotic nuclear divisions 1(MND1)fuels cell cycle progression by activating a KLF6/E2F1 positive feedback loop in lung adenocarcinoma

Background:Considering the increase in the proportion of lung adenocarcinoma(LUAD)cases among all lung cancers and its considerable contribution to cancer-related deaths worldwide,we sought to identify novel oncogenes to provide potential targets and facilitate a better understanding of the malignant progression of LUAD.Methods:The results from the screening of transcriptome and survival analyses according to the integrated Gene Expression Omnibus(GEO)datasets and The Cancer Genome Atlas(TCGA)data were combined,and a promising risk biomarker called meiotic nuclear divisions 1(MND1)was selectively acquired.Cell viability assays and subcutaneous xenograftmodelswere used to validate the oncogenic role ofMND1 in LUADcell proliferation and tumor growth.Aseries of assays,including mass spectrometry,co-immunoprecipitation(Co-IP),and chromatin immunoprecipitation(ChIP),were performed to explore the underlying mechanism.Results:MND1 up-regulation was identified to be an independent risk factor for overall survival in LUAD patients evaluated by both tissue microarray staining and third party data analysis.In vivo and in vitro assays showed that MND1 promoted LUAD cell proliferation by regulating cell cycle.The results of the Co-IP,ChIP and dual-luciferase reporter assays validated that MND1 competitively bound to tumor suppressor Kruppel-like factor 6(KLF6),and thereby protecting E2F transcription factor 1(E2F1)from KLF6-induced transcriptional repression.Luciferase reporter and ChIP assays found that E2F1 activated MND1 transcription by binding to its promoter in a feedback manner.Conclusions:MND1,KLF6,and E2F1 form a positive feedback loop to regulate cell cycle and confer DDP resistance in LUAD.MND1 is crucial for malignant progression and may be a potential therapeutic target in LUAD patients.

Hepatic SIRT6 deficit promotes liver tumorigenesis in the mice models

SIRT6 belongs to class III sirtuin family with NAD+-dependent histone deacetylase activities and controls multiple processes including aging,metabolism and inflammation.In recent years,increasing studies showed tumor suppressor role of SIRT6 in HCC development.We established a two-stage DEN followed CC14 induced liver carcinogenesis in the hepatic-specific SIRT6 HKO mice models and found that hepatic S1RT6 deficit significantly promotes liver injury and liver cancer through inhibition of the ERK1/2 pathway.SIRT6 was compensatory up-regulated in mice tumor tissues and human HCC cells and overexpressed SIRT6 inhibits tumor growth both in vitro and in vivo.Taken together,we provide a useful mouse model for delineating the molecular pathways involved in chronic liver diseases and primary liver cancer and suggest that SIRT6 can be a promising target for HCC therapies.