Involvement of clusterin expression in the refractory response of pancreatic cancer cells to a MEK inhibitor.
Involvement of clusterin expression in the refractory response of pancreatic cancer cells to a MEK inhibitor.
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作者：
丝裂原活化蛋白激酶（MAPK）信号通路的组成性激活是胰腺导管腺癌（PDAC）发生的必要条件。然而，迄今为止，几乎所有针对这一途径的抑制剂的临床试验都未能改善PDAC患者的预后。我们发现植入的MIA Paca2（一种对MAPK抑制剂PD0325901敏感的人PDAC细胞系）在治疗后一周内变得难治性。通过比较获得PD0325901耐受性前后MIA Paca2的表达谱，我们确定了clusterin （CLU）作为候选基因参与其中。CLU在PD0325901处理后立即被诱导，或主要在超过一半的PDAC细胞系中表达，通过避免细胞凋亡来提高细胞活力。PD0325901和CLU下调的组合被发现协同或加性地减少PDAC细胞的增殖。在手术切除的PDAC组织中，在大约一半的研究病例中，免疫组织化学观察到癌细胞中CLU的过表达。总的来说，我们的研究结果强调了PDAC细胞对MEK抑制剂快速难治反应的机制，提出了一种新的治疗策略，可以适用于PDAC患者，使用靶向MAPK信号通路和CLU的抑制剂。我们的研究结果强调了PDAC细胞快速获得对MEK抑制剂耐药的机制，提出了一种新的治疗策略，可以适用于PDAC患者使用靶向MAPK信号通路和CLU的抑制剂。
Constitutive activation of the mitogen‐activated protein kinase (MAPK) signaling pathway is essential for tumorigenesis of pancreatic ductal adenocarcinoma (PDAC). To date, however, almost all clinical trials of inhibitor targeting this pathway have failed to improve the outcome of patients with PDAC. We found that implanted MIA Paca2, a human PDAC cell line sensitive to a MAPK inhibitor, PD0325901, became refractory within a week after treatment. By comparing the expression profiles of MIA Paca2 before and after acquisition of the refractoriness to PD0325901, we identified clusterin (CLU) as a candidate gene involved. CLU was shown to be induced immediately after treatment with PD0325901 or expressed primarily in more than half of PDAC cell lines, enhancing cell viability by escaping from apoptosis. A combination of PD0325901 and CLU downregulation was found to synergistically or additively reduce the proliferation of PDAC cells. In surgically resected PDAC tissues, overexpression of CLU in cancer cells was observed immunohistochemically in approximately half of the cases studied. Collectively, our findings highlight the mechanisms responsible for the rapid refractory response to MEK inhibitor in PDAC cells, suggesting a novel therapeutic strategy that could be applicable to patients with PDAC using inhibitor targeting the MAPK signaling pathway and CLU. Our findings highlight the mechanisms responsible for the rapid acquisition of resistance to MEK inhibitor in PDAC cells, suggesting a novel therapeutic strategy that could be applicable to patients with PDAC using inhibitor targeting the MAPK signaling pathway and CLU.
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影响因子：
28.2
作者：
Collisson EA;Trejo CL;Silva JM;Gu S;Korkola JE;Heiser LM;Charles RP;Rabinovich BA;Hann B;Dankort D;Spellman PT;Phillips WA;Gray JW;McMahon M
通讯作者：
McMahon M
影响因子：
5.7
作者：
Ichimanda M;Hijiya N;Tsukamoto Y;Uchida T;Nakada C;Akagi T;Etoh T;Iha H;Inomata M;Takekawa M;Moriyama M
通讯作者：
Moriyama M
影响因子：
3
作者：
Huijberts, Sanne C. F. A.;van Geel, Robin M. J. M.;Schellens, Jan H. M.
通讯作者：
Schellens, Jan H. M.
DUSP6/MKP-3对FGF信号传导的负反馈调节由ERK1/2驱动，并由ETS因子与DUSP6/MKP-3基因启动子内的保守位点结合介导。
DOI：
10.1042/bj20071512
发表时间：
2008-06-01
期刊：
The Biochemical journal
影响因子：
--
作者：
Ekerot M;Stavridis MP;Delavaine L;Mitchell MP;Staples C;Owens DM;Keenan ID;Dickinson RJ;Storey KG;Keyse SM
通讯作者：
Keyse SM
影响因子：
4.8
作者：
Ammar, Hayet;Closset, Jean L.
通讯作者：
Closset, Jean L.