Boucher M J, Morisset J, Vachon P H, Reed J C, Lainé J, Rivard N
Groupe du Conseil de Recherches Médicales sur le Développement Fonctionnel et la Physiopathologie du Tube Digestif, Département d'Anatomie et Biologie Cellulaire, Université de Sherbrooke, Sherbrooke, Quebec, J1H 5N4, Canada.
J Cell Biochem. 2000 Sep 7;79(3):355-69.
Growth factors are well known for their participation in the regulation of cell proliferation and survival. However, the intracellular signaling pathways by which growth factors promote survival are still poorly understood. In the present study, using the MIA PaCa-2 cell line, a well-established model of pancreatic cancer cells, we analyzed the roles of ERK1/2 activities in the regulation of cell survival and investigated some of the mechanisms involved.
The ability of the MEK inhibitor PD98059 to modulate survival of the MIA PaCa-2 cells was evaluated, and the responses were correlated with expression of Bcl-2 homologs and caspases 1, 3, 6, 8, and 9 activities.
Herein, we showed that inhibition of ERK1/2 activities caused (1) a G1 arrest; (2) a down-regulation of the expression levels of the anti-apoptotic homologs Bcl-2, Mcl-1, and Bcl-X(L) without affecting the pro-apoptotic levels of Bax and Bak; (3) a promotion of caspases 3, 6, 8, and 9 activities; (4) a stimulation of PARP cleavage; and (5) a programmed cell death by apoptosis.
Our data suggest that activation of the ERK pathway functions to protect pancreatic tumor cells from apoptosis as well as to regulate their progression in the cell cycle.
生长因子参与细胞增殖和存活的调控，这一点广为人知。然而，生长因子促进细胞存活的细胞内信号通路仍未被充分了解。在本研究中，我们使用已建立的胰腺癌细胞模型MIA PaCa - 2细胞系，分析了ERK1/2活性在细胞存活调控中的作用，并研究了其中涉及的一些机制。
评估MEK抑制剂PD98059调节MIA PaCa - 2细胞存活的能力，并将反应与Bcl - 2同源物的表达以及半胱天冬酶1、3、6、8和9的活性相关联。
在此，我们表明抑制ERK1/2活性导致（1）G1期阻滞；（2）抗凋亡同源物Bcl - 2、Mcl - 1和Bcl - X(L)的表达水平下调，而不影响促凋亡蛋白Bax和Bak的水平；（3）促进半胱天冬酶3、6、8和9的活性；（4）刺激PARP裂解；以及（5）通过凋亡导致程序性细胞死亡。
我们的数据表明，ERK通路的激活起到保护胰腺肿瘤细胞免于凋亡以及调节其在细胞周期中进展的作用。
