title: BRG1 promotes chemoresistance of pancreatic cancer cells through crosstalking with Akt signalling.
abstract: Gemcitabine is a standard chemotherapeutic agent for locally advanced and metastatic pancreatic cancer. However, the chemoresistance of pancreatic cancer is the major barrier to efficient chemotherapy. Here, we reported that BRG1, a chromatin modulator, was exclusively overexpressed in human pancreatic ductal adenocarcinoma tissues. BRG1 knockdown inhibited PANC-1 and MIA PaCa-2 cell growth in vitro and in vivo, reduced the phosphorylation/activation of Akt and p21(cip/waf), enhanced intrinsic and gemcitabine induced apoptosis and attenuated gemcitabine-induced downregulation of E-cadherin. Moreover, by establishing acquired chemoresistance of MIA PaCa-2 cells in vitro, we found that BRG1 knockdown effectively reversed the chemoresistance to gemcitabine. Surprisingly, inhibiting Akt phosphorylation resulted in BRG1 suppression in pancreatic cancer cells, indicating BRG1 as a new downstream target of Akt signalling. Taken together, our findings suggest that BRG1 promotes both intrinsic and acquired chemoresistance of pancreatic cancer cells, and BRG1 crosstalks with Akt signalling to form a positive feedback loop to promote pancreatic cancer development.
authors: Department of General Surgery, Peking University First Hospital, 8th Xishiku Street, Xicheng, Beijing 100034, People's Republic of China.
authors: Xiaoran
authors: X
authors: Liu
authors: Department of General Surgery, Peking University First Hospital, 8th Xishiku Street, Xicheng, Beijing 100034, People's Republic of China. Electronic address: tianxiaodong976@139.com.
authors: Xiaodong
authors: X
authors: Tian
authors: Department of General Surgery, Peking University First Hospital, 8th Xishiku Street, Xicheng, Beijing 100034, People's Republic of China.
authors: Feng
authors: F
authors: Wang
authors: Department of General Surgery, Peking University First Hospital, 8th Xishiku Street, Xicheng, Beijing 100034, People's Republic of China.
authors: Yongsu
authors: Y
authors: Ma
authors: Clinic of General, Visceral and Transplantation Surgery, University of Ulm, Ulm, Germany.
authors: Marko
authors: M
authors: Kornmann
authors: Department of General Surgery, Peking University First Hospital, 8th Xishiku Street, Xicheng, Beijing 100034, People's Republic of China. Electronic address: yangyinmosci@163.com.
authors: Yinmo
authors: Y
authors: Yang
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004265:DNA Helicases / Q000235:genetics / Q000378:metabolism*; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; C493956:CDKN1A protein, human; D015820:Cadherins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D009687:Nuclear Proteins; D014157:Transcription Factors; D003841:Deoxycytidine; D051057:Proto-Oncogene Proteins c-akt; C084108:SMARCA4 protein, human; D004265:DNA Helicases; D000093542:Gemcitabine
keywords: Akt phosphorylation; BRG1; Chemoresistance; Gemcitabine; Pancreatic cancer