Pancreatic cancer cell proliferation is phosphatidylinositol 3-kinase dependent
Pancreatic cancer cell proliferation is phosphatidylinositol 3-kinase dependent
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DOI：
10.1006/jsre.2000.5833
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发表时间：
2000-05-01
影响因子：
2.2
通讯作者：
Callery, MP
中科院分区：
文献类型：
--
作者：
Perugini, RA;McDade, TP;Callery, MP
背景胰腺癌中发现的基因突变（K-ras，p16，p53）导致不适当的细胞增殖。有丝分裂原通过磷脂酰肌醇3-激酶（PI 3 K）-和/或p44/42-有丝分裂原活化蛋白激酶[p44/42-MAPK或细胞外信号调节激酶（ERK）]信号通路刺激增殖。我们研究了抑制PI 3 K或ERK是否可以限制人胰腺癌的增殖。在静止的人胰腺癌细胞系（BxPC 3和Panc-1）中，通过10%胎牛血清（FCS）刺激增殖。在某些样品中，还加入PD 98059（ERK抑制剂）或LY 294002（PI 3 K抑制剂）。通过蛋白质印迹测定AKT磷酸化（指示PI 3 K活性）和ERK磷酸化（ERK活化）。MTT法测定细胞活力。流式细胞仪检测细胞周期和细胞凋亡，双尾t检验统计学处理（P < 0.05）。LY 294002抑制PI 3 K通路，而不影响ERK激活对血清的响应。PD 98059特异性抑制ERK通路。在BxPC-3和Panc-1细胞系中，LY 294002抑制血清诱导的增殖。PD 98059仅对BxPC 3细胞增殖有抑制作用，且抑制程度低于LY 294002。PI 3 K信号传导似乎是胰腺癌细胞中G（1）-到-S期进展和增殖所必需的。ERK在有丝分裂原诱导的增殖中起较小的作用。PI 3 K的药理学抑制可以减少增殖，增加凋亡，并可能在胰腺癌中提供治疗益处。(C)北京大学出版社.
Background. Genetic mutations found in pancreatic cancer (K-ras, p16, p53) lead to inappropriate cellular proliferation. Mitogens stimulate proliferation via the phosphatidylinositol 3-kinase (PI3K)- and/or the p44/42-mitogen-activate protein kinase [p44/42-MAPK or extracellular signal-regulated kinase (ERK)] signaling pathways. We examined whether inhibition of either PI3K or ERK could limit proliferation in human pancreatic cancer.Methods. Proliferation was stimulated in quiescent human pancreatic cancer cell lines (BxPC3 and Panc-1) by 10% fetal calf serum (FCS), In certain samples, PD98059 (an ERK inhibitor) or LY294002 (a PI3K inhibitor) was also added. AKT phosphorylation (indicating PI3K activity) and ERK phosphorylation (ERK activation) were determined by Western blot. Cell viability was determined by MTT assay. Cell cycle progression and apoptosis were determined by flow cytometry, A two-tailed t test was used for statistical analysis of the data (significance P < 0.05).Results. LY294002 inhibited the PI3K pathway without affecting ERK activation in response to serum. PD98059 inhibited the ERK pathway specifically. In both BxPC-3 and Panc-1 cell lines, LY294002 inhibited serum-induced proliferation. This was associated with G(1) cell cycle arrest and with an increase in the rate of apoptosis, PD98059 inhibited proliferation only in BxPC3 cells, and to a lesser degree than did LY294002,Conclusions. PI3K signaling appears to be necessary for G(1)-to-S phase progression and proliferation in pancreatic cancer cells. ERK plays a lesser role in mitogen-induced proliferation. Pharmacological inhibition of PI3K may decrease proliferation, increase apoptosis, and potentially confer therapeutic benefit in pancreatic cancer. (C) 2000 Academic Press.