BRG1 promotes chemoresistance of pancreatic cancer cells through crosstalking with Akt signalling |
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Institution: | 2. UMR3347, Centre National de la Recherche Scientifique, 91400 Orsay, France;3. U1021, Institut National de la Santé et de la Recherche Médicale, 91400 Orsay, France;4. Université Paris Sud, 91400 Orsay, France;5. Clermont Auvergne University, EA7283 CREaT, 63011 Clermont-Ferrand, France;11. UMR 6293, Centre National de la Recherche Scientifique, 63001 Clermont-Ferrand, France;12. Clermont Auvergne University, GReD Laboratory, Clermont-Ferrand, 63000, France;8. Biostatistics Department, DRCI, Clermont-Ferrand Hospital, Clermont-Ferrand, 63003, France;9. Radiotherapy Department, Institut Curie, 75005 Paris, France |
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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 p21cip/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. |
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Keywords: | Pancreatic cancer BRG1 Akt phosphorylation Gemcitabine Chemoresistance |
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