BRG1 promotes chemoresistance of pancreatic cancer cells through crosstalking with Akt signalling
BRG1 promotes chemoresistance of pancreatic cancer cells through crosstalking with Akt signalling
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BRG1 通过与 Akt 信号传导相互作用促进胰腺癌细胞的化疗耐药性。
DOI：
10.1016/j.ejca.2014.05.017
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发表时间：
2014-09-01
影响因子：
8.4
通讯作者：
Yang, Yinmo
中科院分区：
文献类型：
--
作者：
Liu, Xiaoran;Tian, Xiaodong;Yang, Yinmo
吉西他滨是局部晚期和转移性胰腺癌的标准化疗药物。然而，胰腺癌的化疗耐药性是有效化疗的主要障碍。在这里，我们报道了 BRG1（一种染色质调节剂）仅在人胰腺导管腺癌组织中过度表达。 BRG1 敲低可抑制 PANC-1 和 MIA PaCa-2 细胞的体外和体内生长，减少 Akt 和 p21(cip/waf) 的磷酸化/激活，增强内在细胞凋亡和吉西他滨诱导的细胞凋亡，并减弱吉西他滨诱导的 E-钙粘蛋白下调。此外，通过在体外建立MIA PaCa-2细胞的获得性化疗耐药性，我们发现BRG1敲除有效逆转了对吉西他滨的化疗耐药性。令人惊讶的是，抑制 Akt 磷酸化会导致胰腺癌细胞中 BRG1 受到抑制，表明 BRG1 是 Akt 信号传导的新下游靶点。综上所述，我们的研究结果表明，BRG1 促进胰腺癌细胞的内在和获得性化疗耐药，并且 BRG1 与 Akt 信号传导相互作用形成正反馈环，促进胰腺癌的发展。 (C) 2014 Elsevier Ltd. 保留所有权利。
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. (C) 2014 Elsevier Ltd. All rights reserved.