Gemcitabine triggers a pro-survival response in pancreatic cancer cells through activation of the MNK2/eIF4E pathway
Gemcitabine triggers a pro-survival response in pancreatic cancer cells through activation of the MNK2/eIF4E pathway
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DOI：
10.1038/onc.2012.306
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发表时间：
2013-06-06
期刊：
影响因子：
8
通讯作者：
Sette, C.
中科院分区：
文献类型：
--
作者：
Adesso, L.;Calabretta, S.;Sette, C.
胰腺导管腺癌（PDAC）是一种侵袭性肿瘤疾病。吉西他滨是目前用于PDAC的化疗药物，由于逃逸途径的发展导致化疗耐药性，因此仅产生较小的益处。在此，我们的目的是调查在PDAC细胞获得性耐药的丝裂原活化蛋白激酶相互作用激酶（MNK）/eIF 4 E途径的参与。通过免疫组化筛选PDAC患者队列显示，eIF 4 E磷酸化与疾病分级、疾病早期发作和预后不良相关。在PDAC细胞系中，化疗药物诱导MNK依赖的eIF 4 E磷酸化。重要的是，MNK活性的药理学抑制通过促进细胞凋亡协同增强吉西他滨的细胞抑制作用。RNA干扰（RNAi）实验表明，MNK 2主要负责PDAC细胞中eIF 4 E磷酸化和吉西他滨抗性。此外，我们发现吉西他滨诱导致癌剪接因子SRSF 1的表达和MNK 2b的剪接，MNK 2b是一种剪接变体，其覆盖上游调控途径并赋予对药物的耐药性增加。通过RNAi沉默SRSF 1消除了这种剪接事件，并重现了MNK药理学或遗传抑制对吉西他滨处理细胞中eIF 4 E磷酸化和凋亡的影响。我们的研究结果强调了一种新的促生存途径触发的吉西他滨在PDAC细胞，这导致MNK 2依赖性磷酸化的eIF 4 E，这表明MNK/eIF 4 E途径代表了一种逃逸途径利用PDAC细胞耐受化疗治疗。
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive neoplastic disease. Gemcitabine, the currently used chemotherapeutic drug for PDAC, elicits only minor benefits, because of the development of escape pathways leading to chemoresistance. Herein, we aimed at investigating the involvement of the mitogen activating protein kinase interacting kinase (MNK)/eIF4E pathway in the acquired drug resistance of PDAC cells. Screening of a cohort of PDAC patients by immunohistochemistry showed that eIF4E phosphorylation correlated with disease grade, early onset of disease and worse prognosis. In PDAC cell lines, chemotherapeutic drugs induced MNK-dependent phosphorylation of eIF4E. Importantly, pharmacological inhibition of MNK activity synergistically enhanced the cytostatic effect of gemcitabine, by promoting apoptosis. RNA interference (RNAi) experiments indicated that MNK2 is mainly responsible for eIF4E phosphorylation and gemcitabine resistance in PDAC cells. Furthermore, we found that gemcitabine induced the expression of the oncogenic splicing factor SRSF1 and splicing of MNK2b, a splice variant that overrides upstream regulatory pathways and confers increased resistance to the drug. Silencing of SRSF1 by RNAi abolished this splicing event and recapitulated the effects of MNK pharmacological or genetic inhibition on eIF4E phosphorylation and apoptosis in gemcitabine-treated cells. Our results highlight a novel pro-survival pathway triggered by gemcitabine in PDAC cells, which leads to MNK2-dependent phosphorylation of eIF4E, suggesting that the MNK/eIF4E pathway represents an escape route utilized by PDAC cells to withstand chemotherapeutic treatments.