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Growth suppression and radiosensitivity increase by HMGB1 in breast cancer

Acta Pharmacologica Sinica 2007年第12期28卷 1957-1967页

作者： Yang JIAO~2,Hai-chao WANG~3,Sai-jun FAN~(2,4,5)~2 school of Radiology and Public Health,Soochow university,Suzhou 215123,China ~3.department of emergency medicine,north shoreuniversity hospital,new york university school of medicine,manhasset,new york 1103.,usa ~4 department of Oncology,LombardiComprehensive Cancer Center,Georgetown university,Washington DC,Washington 20057,usa school of Radiology and Public Health Soochow UniversitySuzhou 215123China department of emergency medicine North Shore University HospitalNew York University School of MedicineManhassetNew York 11030USA department of Oncology Lombardi Comprehe

Aim:HMGB 1 （high-mobility group box-1） is a nuclear protein containing a con-sensus RB （retinoblastoma）-binding LXCXE *** this study,we studied thepotential association of HMGB 1 and RB and the in vitro and in vivo activities ofHMGB 1 in human breast cancer ***:The protein-protein interactionwas determined by immunoprecipitation-Western blotting and glutathione-S-trans-ferase capture assays;cell growth and radiosensitivity were examined by cellcounts,MTT assay,and clonogenic assay;cell cycle progression and apoptosiswere evaluated using flow cytometry;and the antitumor activity of HMGB 1 wasexamined with tumor xenografts in nude ***:HMGB 1 was associatedwith RB via a LXCXE motif-dependent *** 1 enhanced the abilityof RB for E2F and cyclin A transcription *** increased expression ofHMGB 1 conferred an altered phenotypes characterized by the suppression of cellgrowth;G1arrest and apoptosis was induced in MCF-7 cells containing the wild-type retinoblastoma （Rb） gene,but showed no activities in BT-549 cells contain-ing the Rb gene *** HMGB 1-induced apoptosis accompanied by caspase3 activation and PARP (poly（ADP-ribose）polymerase) *** 1 elevatedthe radiosensitivity of breast cancer cells in both the MCF-7 and BT-549 cell *** enhanced expression of HMGB 1 caused a suppression of growth of MCF-7tumor xenografts in nude mice,while LXCXE-defective HMGB 1 completely lostantitumor growth ***:HMGB 1 functions as a tumor suppressorand radiosensitizer in breast cancer.A HMGB 1-RB interaction is critical for theHMGB 1-mediated transcriptional repression,cell growth inhibition,G1cell cyclearrest,apoptosis induction,and tumor growth suppression,but is not required ***,it may be possible to design new therapies for thetreatment of breast cancer that exert their effects by modulating the HMGB 1 andRB regulatory pathway and HMGB 1-related gene therapy.

关键词： HMGBI RB breast cancer cell growth

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