Aldehyde dehydrogenase 1A1 confers intrinsic and acquired resistance to gemcitabine in human pancreatic adenocarcinoma MIA PaCa-2 cells.
Aldehyde dehydrogenase 1A1 confers intrinsic and acquired resistance to gemcitabine in human pancreatic adenocarcinoma MIA PaCa-2 cells.
复制标题
DOI：
10.3892/ijo.2012.1516
复制
发表时间：
2012-09
影响因子：
5.2
通讯作者：
Bae I
中科院分区：
文献类型：
--
作者：
Duong HQ;Hwang JS;Kim HJ;Kang HJ;Seong YS;Bae I
吉西他滨（GEM）是用于治疗胰腺癌的一线标准化疗药物;然而，对GEM的耐药性仍然是成功控制这种疾病的主要障碍。乙醛脱氢酶1A 1（ALDH 1A 1）的表达水平和活性是多种类型人类癌症中肿瘤起始和/或癌症干细胞性质的重要特征。由于癌症干细胞的内在特性之一是耐药性，在这项研究中，我们研究了内源性ALDH 1A 1的水平和活性与含有高表达水平和活性ALDH 1A 1的MIA PaCa-2细胞系中GEM耐药性之间的相关性。我们使用小干扰RNA（siRNA）来消耗ALDH 1A 1并研究其在赋予GEM抗性中的潜在作用。ALDH 1A 1敲低显著降低ALDH 1A 1表达和活性，并抑制细胞增殖。此外，与对照组相比，ALDH 1A 1-siRNA和GEM的组合显著降低了细胞活力，增加了凋亡性细胞死亡，并增加了细胞在S期的积累。我们的数据还表明，与亲本MIA PaCa-2细胞系（MIA PaCa-2/P）相比，在GEM抗性MIA PaCa-2细胞系（MIA PaCa-2/GR）中ALDH 1A 1表达和活性显著更高。在MIA PaCa-2/GR细胞中，ALDH 1A 1-siRNA和GEM的组合也显示出细胞活力的显著降低和凋亡性细胞死亡的增加，强调了ALDH 1A 1在内在和获得性GEM抗性中的重要性。ALDH 1A 1-siRNA和GEM的这种潜在的强大组合治疗值得进一步研究，作为克服胰腺癌对GEM的抗性的有效治疗方案。
Gemcitabine (GEM) is the front-line standard chemotherapy used for the treatment of pancreatic cancer; however, chemoresistance to GEM remains the major obstacle to the successful control of this disease. Both the expression levels and activity of aldehyde dehydrogenase 1A1 (ALDH1A1) are important features of tumor-initiating and/or cancer stem cell properties in multiple types of human cancer. As one of the intrinsic properties of cancer stem cells is drug resistance, in this study, we examined the correlation between the level and activity of endogenous ALDH1A1 and GEM resistance in the MIA PaCa-2 cell line that contains high expression levels and activity of ALDH1A1. We used small interfering RNAs (siRNAs) to deplete ALDH1A1 and investigate its potential role in conferring GEM resistance. The ALDH1A1 knockdown markedly reduced ALDH1A1 expression and activity and inhibited cell proliferation. Moreover, the combination of ALDH1A1-siRNA and GEM significantly decreased cell viability, increased apoptotic cell death and increased the accumulation of cells at the S-phase compared to the controls. Our data also demonstrated that ALDH1A1 expression and activity were significantly higher in the GEM-resistant MIA PaCa-2 cell line (MIA PaCa-2/GR), compared to the parental MIA PaCa-2 cell line (MIA PaCa-2/P). In the MIA PaCa-2/GR cells, the combination of ALDH1A1-siRNA and GEM also showed a significant decrease in cell viability and an increase in apoptotic cell death, emphasizing the importance of ALDH1A1 in both intrinsic and acquired GEM resistance. This potentially powerful combination treatment of ALDH1A1-siRNA and GEM warrants further investigation as an effective therapeutic regimen to overcome the resistance of pancreatic cancer to GEM.
登录
查看更多内容
影响因子：
11.2
作者：
Huang EH;Hynes MJ;Zhang T;Ginestier C;Dontu G;Appelman H;Fields JZ;Wicha MS;Boman BM
通讯作者：
Boman BM
影响因子：
12.4
作者：
Kallifatidis, Georgios;Labsch, Sabrina;Herr, Ingrid
通讯作者：
Herr, Ingrid
影响因子：
45.3
作者：
Cunningham, David;Chau, Ian;Neoptolemos, John P.
通讯作者：
Neoptolemos, John P.
影响因子：
29.4
作者：
Ma, Stephanie;Chan, Kwok-Wah;Guan, Xin-Yuan
通讯作者：
Guan, Xin-Yuan
胰腺腺癌中缓慢循环干细胞样亚群的表征和功能分析。
影响因子：
4
作者：
Dembinski, Jennifer L.;Krauss, Stefan
通讯作者：
Krauss, Stefan