Chloroquine plays a cell-dependent role in the response to treatment of pancreatic adenocarcinoma.
Chloroquine plays a cell-dependent role in the response to treatment of pancreatic adenocarcinoma.
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DOI：
10.18632/oncotarget.25745
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发表时间：
2018-07-20
期刊：
影响因子：
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通讯作者：
Iovanna, Juan
中科院分区：
文献类型：
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作者：
Molejon, Maria Ines;Swayden, Mirna;Iovanna, Juan
在这项研究中，我们的目的是评估自噬及其抑制在不同PDAC细胞区室中所起的作用，以及其在使用原代人胰腺癌衍生细胞（PCC）和癌症相关成纤维细胞（CAF）的化学抗性中的作用。自噬通量，如通过LC 3-I和-II在氯喹的存在下测量的，在PCC和CAFs中显示可变水平。我们发现自噬水平和肿瘤分化程度之间没有相关性。氯喹与吉西他滨、5 FU、奥沙利铂、伊立替康和多西他赛的联合显示，其对存活的影响在体外和体内具有细胞和药物依赖性。此外，我们证明了CAFs中的自噬可以在PDAC对抗癌治疗的敏感性方面发挥重要作用，因为其抑制增加了PCC对吉西他滨的耐药性。总之，这项工作清楚地表明了氯喹作用的异质性，并强调了CAFs自噬在使肿瘤对治疗敏感中的作用。它还揭示了自噬在PDAC中的作用及其对治疗的敏感性比预期的更复杂。
In this study, our aim is to assess the role played by autophagy and its inhibition in the different PDAC cellular compartments, and its involvement in chemo-resistance using primary human pancreatic cancer-derived cells (PCC) and Cancer Associated Fibroblasts (CAF). Autophagy flux, as measured by LC3-I and -II in the presence of Chloroquine, showed a variable level in PCC and CAFs. We found no correlation between autophagy level and degree of tumor differentiation. Association of Chloroquine with gemcitabine, 5FU, oxaliplatin, irinotecan and docetaxel revealed that its effect on survival is cell- and drug-dependent in vitro and in vivo. In addition, we demonstrated that autophagy in CAFs can play an important role in sensitizing PDAC to anticancer treatments since its inhibition increased the resistance of PCCs to gemcitabine. In conclusion, this work clearly shows a heterogeneity in the effect of Chloroquine and highlights a role of CAFs autophagy in sensitizing tumors to treatments. It also reveals that the role of autophagy is more complex than expected in PDAC as well as its sensitivity to treatments.