Overexpression of HMGA1 promotes anoikis resistance and constitutive Akt activation in pancreatic adenocarcinoma cells.
Overexpression of HMGA1 promotes anoikis resistance and constitutive Akt activation in pancreatic adenocarcinoma cells.
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DOI：
10.1038/sj.bjc.6603654
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发表时间：
2007-03-26
影响因子：
8.8
通讯作者：
Whang, E. E.
中科院分区：
文献类型：
--
作者：
Liau, S-S;Jazag, A.;Ito, K.;Whang, E. E.
HMGA1 蛋白是胰腺腺癌过度表达的结构转录因子。 HMGA1 在介导这种癌症恶性表型中的作用尚不清楚。我们测试了以下假设：HMGA1 的过度表达会促进胰腺癌细胞对失巢凋亡（锚定剥夺诱导的细胞凋亡）的抵抗。 HMGA1 cDNA 稳定转染至 MiaPaCa2 人胰腺腺癌细胞（HMGA1 基线表达水平较低）。细胞在PolyHEMA包被的板上悬浮生长，并使用流式细胞术测定它们对失巢凋亡的敏感性。 HMGA1 的过表达与失巢凋亡敏感性的显着降低相关，同时与 Akt 磷酸化 (Ser473) 和 Akt 激酶活性的增加以及 caspase 3 激活的减少相一致。使用小分子抑制剂 LY294002 或显性失活 Akt 抑制磷酸肌醇 3 (PI3-K)/Akt 通路，可逆转 HMGA1 过表达诱导的失巢凋亡抵抗。此外，MiaPaCa2 和 BxPC3（一种具有高基线 HMGA1 表达水平的人胰腺腺癌细胞系）细胞中 RNA 干扰介导的 HMGA1 沉默导致失巢凋亡的易感性显着增加。我们的研究结果表明 HMGA1 通过 PI3-K/Akt 依赖性机制促进失巢凋亡抵抗。鉴于失巢凋亡抵抗与转移潜力之间的假定关联，HMGA1 代表了胰腺癌的潜在治疗靶点。
HMGA1 proteins are architectural transcription factors that are overexpressed by pancreatic adenocarcinomas. Roles of HMGA1 in mediating the malignant phenotype of this cancer are poorly understood. We tested the hypothesis that overexpression of HMGA1 promotes resistance to anoikis (apoptosis induced by anchorage deprivation) in pancreatic cancer cells. HMGA1 cDNA was stably transfected into MiaPaCa2 human pancreatic adenocarcinoma cells (which have low baseline expression levels of HMGA1). Cells were grown in suspension on PolyHEMA-coated plates and their susceptibility to anoikis was assayed using flow cytometry. Overexpression of HMGA1 was associated with marked reductions in susceptibility to anoikis in concert with increases in Akt phosphorylation (Ser473) and in Akt kinase activity and with reductions in caspase 3 activation. Inhibition of phosphoinositidyl-3 (PI3-K)/Akt pathway with either the small molecule inhibitor LY294002 or dominant-negative Akt resulted in reversal of anoikis resistance induced by HMGA1 overexpression. Further, RNA interference-mediated HMGA1 silencing in MiaPaCa2 and BxPC3 (a human pancreatic adenocarcinoma cell line with high baseline levels of HMGA1 expression) cells resulted in significant increases in susceptibility to anoikis. Our findings suggest HMGA1 promotes anoikis resistance through a PI3-K/Akt-dependent mechanism. Given the putative associations between anoikis resistance and metastatic potential, HMGA1 represents a potential therapeutic target in pancreatic adenocarcinoma.
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影响因子：
2
作者：
Chuma, Makoto;Saeki, Norihisa;Sakamoto, Michiie
通讯作者：
Sakamoto, Michiie
影响因子：
11.5
作者：
Chiappetta, G;Botti, G;Fusco, A
通讯作者：
Fusco, A
DOI：
10.1073/pnas.070029997
发表时间：
2000-04-11
影响因子：
11.1
作者：
Scala, S;Portella, G;Fusco, A
通讯作者：
Fusco, A
影响因子：
14.9
作者：
FRIEDMANN, M;HOLTH, LT;REEVES, R
通讯作者：
REEVES, R
影响因子：
11.2
作者：
Xu, Y;Sumter, TF;Resar, LMS
通讯作者：
Resar, LMS