CQ sensitizes human pancreatic cancer cells to gemcitabine through the lysosomal apoptotic pathway via reactive oxygen species.
CQ sensitizes human pancreatic cancer cells to gemcitabine through the lysosomal apoptotic pathway via reactive oxygen species.
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CQ 通过活性氧的溶酶体凋亡途径使人胰腺癌细胞对吉西他滨敏感
DOI：
10.1002/1878-0261.12179
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发表时间：
2018-04
影响因子：
6.6
通讯作者：
Qiu W
中科院分区：
文献类型：
--
作者：
Fu Z;Cheng X;Kuang J;Feng H;Chen L;Liang J;Shen X;Yuen S;Peng C;Shen B;Jin Z;Qiu W
吉西他滨（GEM）作为一种成熟的抗肿瘤药物，是治疗晚期胰腺癌（PC）的有效全身治疗药物。然而，很少有人知道的潜在效应，可能会改变肿瘤细胞对GEM的敏感性。自噬作为一种生理细胞机制，参与细胞的生存和死亡。在这项研究中，我们发现暴露于GEM以剂量依赖性方式诱导PANC-1和BxPC-3细胞中自噬的显著增加。氯喹（CQ）和ATG 7 siRNA抑制自噬增加了GEM诱导的细胞毒性，CQ比ATG 7 siRNA更有效。此外，CQ显著增强GEM诱导的凋亡，而ATG 7 siRNA未能显示类似的效果。随后，我们确定了一个潜在的机制，这种合作的相互作用表明，创业板与CQ预处理显着触发活性氧（ROS）的提高，然后增加溶酶体膜的通透性。因此，从溶酶体释放到细胞质中的组织蛋白酶诱导细胞凋亡。我们发现CQ可以增强PC细胞在异种移植模型中对GEM的反应。总之，我们的数据表明，CQ敏化PC细胞GEM通过溶酶体凋亡途径通过ROS。因此，CQ作为GEM的潜在佐剂可能代表PC治疗的有吸引力的治疗策略。
As an established anticancer drug, gemcitabine (GEM) is an effective systemic treatment for advanced pancreatic cancer (PC). However, little is known about the potential effectors that may modify tumour cell sensitivity towards GEM. Autophagy, as a physiological cellular mechanism, is involved in both cell survival and cell death. In this study, we found that exposure to GEM induced a significant increase in autophagy in a dose‐dependent manner in PANC‐1 and BxPC‐3 cells. Inhibition of autophagy by chloroquine (CQ) and ATG7 siRNA increased GEM‐induced cytotoxicity, and CQ was more effective than ATG7 siRNA. Moreover, CQ significantly enhanced GEM‐induced apoptosis, while ATG7 siRNA failed to show the similar effect. Subsequently, we identified a potential mechanism of this cooperative interaction by showing that GEM with CQ pretreatment markedly triggered reactive oxygen species (ROS) boost and then increased lysosomal membrane permeability. Consequently, cathepsins released from lysosome into the cytoplasm induced apoptosis. We showed that CQ could enhance PC cells response to GEM in xenograft models. In conclusion, our data showed that CQ sensitized PC cells to GEM through the lysosomal apoptotic pathway via ROS. Thus, CQ as a potential adjuvant to GEM might represent an attractive therapeutic strategy for PC treatment.
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影响因子：
7.8
作者：
Degtyarev, Michael;De Maziere, Ann;Orr, Christine;Lin, Jie;Lee, Brian B.;Tien, Janet Y.;Prior, Wei W.;van Dijk, Suzanne;Wu, Hong;Gray, Daniel C.;Davis, David P.;Stern, Howard M.;Murray, Lesley J.;Hoeflich, Klaus P.;Klumperman, Judith;Friedman, Lori S.;Lin, Kui
通讯作者：
Lin, Kui
影响因子：
4.8
作者：
Demers-Lamarche, Julie;Guillebaud, Gerald;Germain, Marc
通讯作者：
Germain, Marc
影响因子：
78.5
作者：
Mathew, Robin;Karantza-Wadsworth, Vassiliki;White, Eileen
通讯作者：
White, Eileen
影响因子：
4.2
作者：
Du, Hailei;Yang, Weiping;Qiu, Weihua
通讯作者：
Qiu, Weihua
影响因子：
64.8
作者：
Kuma, A;Hatano, M;Mizushima, N
通讯作者：
Mizushima, N