Effects of triggers of senescence and senolysis in murine pancreatic cancer cells  

作　　者：Denis Revskij Aline Woitas Bianca Kölle Camilla Umstätter Dietmar Zechner Faiz M Khan Georg Fuellen Robert Jaster 

机构地区：[1]Department of MedicineⅡ,Division of Gastroenterology,Rostock University Medical Center,Rostock,Germany [2]Rudolf-Zenker-Institute of Experimental Surgery,Rostock University Medical Center,Rostock,Germany [3]Department of Systems Biology and Bioinformatics,Institute of Computer Science,University of Rostock,Rostock,Germany [4]Institute for Biostatistics and Informatics in Medicine and Ageing Research,Rostock University Medical Center,Rostock,Germany

出　　处：《Hepatobiliary & Pancreatic Diseases International》2024年第6期628-637,共10页国际肝胆胰疾病杂志（英文版）

基　　金：supported by a grant from the Bundesministerium fur Bildung und Forschung(01ZX1903A).

摘　　要：Background:The combination of senescence triggers with senolytic drugs is considered a promising new approach to cancer therapy.Here,we studied the efficacy of the genotoxic agent etoposide(Eto)and irradiation in inducing senescence of Panc02 pancreatic cancer cells,and the capability of the Bcl-2 inhibitor navitoclax(ABT-263;Nav)to trigger senolysis.Methods:Panc02 cells were treated with Eto or irradiated with 5–20 Gy before exposure to Nav.Cell survival,proliferation,and senescence were assessed by trypan blue staining,quantification of DNA synthesis,and staining of senescence-associatedβ-galactosidase(SA-β-Gal)-positive cells,respectively.Levels of mRNA were determined by real-time polymerase chain reaction,and protein expression was analyzed by immunoblotting.Panc02 cells were also grown as pancreatic tumors in mice,which were subsequently treated with Eto and Nav.Results:Eto and irradiation had an antiproliferative effect on Panc02 cells that was significantly or tendentially enhanced by Nav.In vivo,Eto and Nav together,but not Eto alone,significantly reduced the proportion of proliferating cells.The expression of the senescence markerγH2AX and tumor infiltration with T-cells were not affected by the treatment.In vitro,almost all Eto-exposed cells and a significant proportion of cells irradiated with 20 Gy were SA-β-Gal-positive.Application of Nav reduced the percentage of SA-β-Gal-positive cells after irradiation but not after pretreatment with Eto.In response to triggers of senescence,cultured Panc02 cells showed increased protein levels ofγH2AX and the autophagy marker LC3B-II,and higher mRNA levels of Cdkn1a,Mdm2,and PAI-1,while the effects of Nav were variable.Conclusions:In vitro and in vivo,the combination of senescence triggers with Nav inhibited tumor cell growth more effectively than the triggers alone.Our data also provide some evidence for senolytic effects of Nav in vitro.

关 键 词：Pancreatic cancer Panc02 cells ETOPOSIDE IRRADIATION Navitoclax 

分 类 号：R735.9[医药卫生—肿瘤]