ROS/KRAS/AMPK Signaling Contributes to Gemcitabine-Induced Stem-like Cell Properties in Pancreatic Cancer
ROS/KRAS/AMPK Signaling Contributes to Gemcitabine-Induced Stem-like Cell Properties in Pancreatic Cancer
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ROS/KRAS/AMPK 信号传导有助于吉西他滨诱导胰腺癌的干细胞特性
DOI：
10.1016/j.omto.2019.07.005
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发表时间：
2019-08
影响因子：
5.7
通讯作者：
Yin Tao
中科院分区：
文献类型：
--
作者：
Zhao Hengqiang;Wu Shihong;Li Hehe;Duan Qingke;Zhang Zhengle;Shen Qiang;Wang Chunyou;Yin Tao
胰腺癌（PANCA）的预后不良部分是由于对吉西他滨（GEM）的化学抗性。葡萄糖代谢已揭示出有助于panca细胞的治疗耐药性和多能状态。然而，很少有研究集中在宝石对癌细胞代谢，肿瘤细胞的干性以及严重影响PANCA治疗的分子机制上的影响。我们证明，GEM处理可诱导代谢重编程，减少线粒体氧化和上调有氧糖酵解，并促进癌细胞中的茎样行为。抑制有氧糖酵解可抑制癌细胞的干性并增强宝石的细胞毒性。由于敲除kras的敲低反向代谢转移，宝石诱导的代谢重编程依赖于ISKRASDENTENT。宝石诱导的代谢重编程还激活了AMP激活的蛋白激酶（AMPK），该蛋白激酶（AMPK）促进糖酵解通量和癌症。此外，宝石诱导的活性氧（ROS）激活了KRAS/AMPK途径。通过引入过氧化氢（H2O2）来验证这种作用。综上所述，这些发现揭示了panca治疗期间的适得其反的宝石作用。调节细胞氧化还原，靶向KRAS/AMPK信号传导或逆转代谢重编程可能是消除癌症干细胞（CSC）的有效方法，并提高对GEM的化学敏感性以改善PANCA患者的预后。
Poor prognosis in pancreatic cancer (PanCa) is partially due to chemoresistance to gemcitabine (GEM). Glucose metabolism has been revealed to contribute to the therapeutic resistance and pluripotent state of PanCa cells. However, few studies have focused on the effects of GEM on cancer cell metabolism, stemness of tumor cells, and molecular mechanisms that critically influence PanCa treatment. We demonstrate that GEM treatment induces metabolic reprogramming, reducing mitochondrial oxidation and upregulating aerobic glycolysis, and promotes stem-like behaviors in cancer cells. Inhibiting aerobic glycolysis suppresses cancer cell stemness and strengthens GEM's cytotoxicity. GEM-induced metabolic reprogramming isKRASdependent, as knockdown ofKRASreverses the metabolic shift. GEM-induced metabolic reprogramming also activates AMP-activated protein kinase (AMPK), which promotes glycolytic flux and cancer stemness. In addition, GEM-induced reactive oxygen species (ROS) activate the KRAS/AMPK pathway. This effect was validated by introducing exogenous hydrogen peroxide (H2O2). Taken together, these findings reveal a counterproductive GEM effect during PanCa treatment. Regulating cellular redox, targeting KRAS/AMPK signaling, or reversing metabolic reprogramming might be effective approaches to eliminate cancer stem cells (CSCs) and enhance chemosensitivity to GEM to improve the prognosis of PanCa patients.
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影响因子：
64.8
作者：
Viale, Andrea;Pettazzoni, Piergiorgio;Lyssiotis, Costas A.;Ying, Haoqiang;Sanchez, Nora;Marchesini, Matteo;Carugo, Alessandro;Green, Tessa;Seth, Sahil;Giuliani, Virginia;Kost-Alimova, Maria;Muller, Florian;Colla, Simona;Nezi, Luigi;Genovese, Giannicola;Deem, Angela K.;Kapoor, Avnish;Yao, Wantong;Brunetto, Emanuela;Kang, Ya'an;Yuan, Min;Asara, John M.;Wang, Y. Alan;Heffernan, Timothy P.;Kimmelman, Alec C.;Wang, Huamin;Fleming, Jason B.;Cantley, Lewis C.;DePinho, Ronald A.;Draetta, Giulio F.
通讯作者：
Draetta, Giulio F.
影响因子：
5.2
作者：
Folmes CDL;Nelson TJ;Dzeja PP;Terzic A
通讯作者：
Terzic A
影响因子：
3.1
作者：
Du, Zhiyong;Qin, Renyi;Peng, Chenghong
通讯作者：
Peng, Chenghong
糖酵解上调促进吉西他滨耐药胰腺癌细胞的干性和 EMT 表型
影响因子：
5.3
作者：
Zhao H;Duan Q;Zhang Z;Li H;Wu H;Shen Q;Wang C;Yin T
通讯作者：
Yin T
DOI：
10.1126/science.1174229
发表时间：
2009-09-18
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Yun J;Rago C;Cheong I;Pagliarini R;Angenendt P;Rajagopalan H;Schmidt K;Willson JK;Markowitz S;Zhou S;Diaz LA Jr;Velculescu VE;Lengauer C;Kinzler KW;Vogelstein B;Papadopoulos N
通讯作者：
Papadopoulos N