The P2Y2/Src/p38/COX-2 pathway is involved in the resistance to ursolic acid-induced apoptosis in colorectal and prostate cancer cells
The P2Y2/Src/p38/COX-2 pathway is involved in the resistance to ursolic acid-induced apoptosis in colorectal and prostate cancer cells
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DOI：
10.1016/j.biochi.2012.04.006
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发表时间：
2012-08-01
期刊：
影响因子：
3.9
通讯作者：
Liagre, Bertrand
中科院分区：
文献类型：
--
作者：
Limami, Youness;Pinon, Aline;Liagre, Bertrand
癌症的特征之一是抵抗细胞凋亡。阐明癌细胞如何逃避或延迟细胞凋亡的机制将导致新的治疗策略。先前，我们发现HT-29结直肠癌细胞在p38依赖途径中过度表达环氧化酶-2 (COX-2)，以延缓熊果酸诱导的细胞凋亡。在这里，我们重点阐明调控这种抗性机制的上游信号通路。ATP作为细胞外信号分子的作用经过了很长时间才被接受。近年来，ATP及其类似物通过激活特定的嘌呤能受体，参与了许多生物过程，包括细胞增殖、分化和凋亡。在本报告中，我们已经证明了嘌呤能受体，特别是P2Y(2)受体在熊果酸诱导的结直肠癌HT-29和前列腺DU145癌细胞凋亡抗性中的新作用。我们发现熊果酸诱导细胞内ATP和P2Y(2)转录物水平的增加。激活后，P2Y(2)激活Src，进而使p38磷酸化，导致COX-2过表达，从而在HT-29和DU145细胞中诱导对凋亡的抵抗。此外，Ca2+非依赖性PLA(2) （iPLA(2)）和Ca2+依赖性分泌PLA(2) （sPLA(2)）负责花生四烯酸的释放，COX-2的底物。我们的研究结果表明，熊果酸处理后，两种细胞系的凋亡触发依赖于蛋白激酶C （PKC）的激活。(C) 2012 Elsevier Masson SAS。版权所有。
One of the hallmarks of cancer is resistance to apoptosis. Elucidating the mechanisms of how cancer cells evade or delay apoptosis should lead to novel therapeutic strategies. Previously, we showed that HT-29 colorectal cancer cells undergoing apoptosis overexpressed cyclooxygenase-2 (COX-2), in a p38 dependent pathway, to delay ursolic acid-induced apoptosis. Here, we focused on elucidating the upstream signaling pathways regulating this resistance mechanism. The role of ATP as an extracellular signaling molecule took a long time to be accepted. In recent years, ATP and its analogs, via the activation of specific purinergic receptors, have been implicated in many biological processes including cell proliferation, differentiation and apoptosis. In the present report, we have demonstrated a novel role involving purinergic receptors and particularly the P2Y(2) receptor in resistance to ursolic acid-induced apoptosis in both colorectal HT-29 and prostate DU145 cancer cells. We found that ursolic acid induced an increase in intracellular ATP and P2Y(2) transcript levels. Upon activation, P2Y(2) activated Src which in turn phosphorylated p38 leading to COX-2 overexpression which induced resistance to apoptosis in both HT-29 and DU145 cells. Furthermore, Ca2+-independent PLA(2) (iPLA(2)) and Ca2+-dependent secretory PLA(2) (sPLA(2)) were responsible for arachidonic acid release, the substrate of COX-2. Our findings document that apoptosis triggering was dependent on protein kinase C (PKC) activation in both cell lines after ursolic acid treatment. (C) 2012 Elsevier Masson SAS. All rights reserved.