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ROS/KRAS/AMPK信号通路促成吉西他滨诱导的胰腺癌干细胞样特性

ROS/KRAS/AMPK Signaling Contributes to Gemcitabine-Induced Stem-like Cell Properties in Pancreatic Cancer.

作者信息

Zhao Hengqiang, Wu Shihong, Li Hehe, Duan Qingke, Zhang Zhengle, Shen Qiang, Wang Chunyou, Yin Tao

机构信息

Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.

Department of Breast and Thyroid Surgery, Renmin Hospital of Wuhan University, Wuhan 430060, China.

出版信息

Mol Ther Oncolytics. 2019 Aug 9;14:299-312. doi: 10.1016/j.omto.2019.07.005. eCollection 2019 Sep 27.

DOI:10.1016/j.omto.2019.07.005
PMID:31508487
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6726755/
Abstract

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 is dependent, as knockdown of reverses 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 (HO). 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.

摘要

胰腺癌（PanCa）预后较差部分归因于对吉西他滨（GEM）的化疗耐药性。已发现葡萄糖代谢有助于胰腺癌细胞的治疗耐药性和多能状态。然而，很少有研究关注吉西他滨对癌细胞代谢、肿瘤细胞干性以及对胰腺癌治疗有关键影响的分子机制的作用。我们证明，吉西他滨治疗可诱导代谢重编程，减少线粒体氧化并上调有氧糖酵解，并促进癌细胞的干性样行为。抑制有氧糖酵解可抑制癌细胞干性并增强吉西他滨的细胞毒性。吉西他滨诱导的代谢重编程是依赖于 的，因为敲低 可逆转代谢转变。吉西他滨诱导的代谢重编程还激活AMP激活的蛋白激酶（AMPK），促进糖酵解通量和癌症干性。此外，吉西他滨诱导的活性氧（ROS）激活KRAS/AMPK途径。通过引入外源性过氧化氢（HO）验证了这种效应。综上所述，这些发现揭示了吉西他滨在胰腺癌治疗过程中产生的适得其反的效果。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（CSCs）并增强对吉西他滨的化学敏感性以改善胰腺癌患者预后的有效方法。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/184b/6726755/c84aa736f296/gr9.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/184b/6726755/9d614ef3e05d/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/184b/6726755/7bbe5901f0d8/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/184b/6726755/ab19a1886463/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/184b/6726755/6c6661a9abb8/gr4.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/184b/6726755/f40e2ff8f8ee/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/184b/6726755/69948c0430fe/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/184b/6726755/8a7643ad5cd5/gr8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/184b/6726755/c84aa736f296/gr9.jpg

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本文引用的文献

1
Mitochondrial pyruvate carrier function determines cell stemness and metabolic reprogramming in cancer cells.线粒体丙酮酸载体功能决定癌细胞的细胞干性和代谢重编程。
Oncotarget. 2017 Jul 11;8(28):46363-46380. doi: 10.18632/oncotarget.18199.
2
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J Cell Mol Med. 2017 Sep;21(9):2055-2067. doi: 10.1111/jcmm.13126. Epub 2017 Feb 28.
3
Induction of metastasis, cancer stem cell phenotype, and oncogenic metabolism in cancer cells by ionizing radiation.
载有α-十四烷氧羰基吉西他滨的脂质体用于胰腺癌化疗的抗肿瘤效率提高
Int J Nanomedicine. 2024 Dec 11;19:13391-13410. doi: 10.2147/IJN.S485861. eCollection 2024.
4
The role of AMPK in pancreatic cancer: from carcinogenesis to treatment.AMPK在胰腺癌中的作用：从致癌作用到治疗
Clin Transl Oncol. 2025 Jan;27(1):70-82. doi: 10.1007/s12094-024-03572-8. Epub 2024 Jun 26.
5
Cordycepin Enhanced Therapeutic Potential of Gemcitabine against Cholangiocarcinoma via Downregulating Cancer Stem-Like Properties.虫草素通过下调癌症干细胞样特性增强吉西他滨对胆管癌的治疗潜力。
Biomol Ther (Seoul). 2024 May 1;32(3):369-378. doi: 10.4062/biomolther.2023.198. Epub 2024 Apr 9.
6
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7
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电离辐射诱导癌细胞发生转移、癌症干细胞表型及致癌代谢。
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4
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5
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Exp Suppl. 2016;107:203-226. doi: 10.1007/978-3-319-43589-3_9.
6
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Biochim Biophys Acta. 2016 Dec;1866(2):177-188. doi: 10.1016/j.bbcan.2016.09.001. Epub 2016 Sep 4.
7
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8
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9
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Oncotarget. 2016 Aug 30;7(35):56324-56337. doi: 10.18632/oncotarget.10838.
10
Cancer stem cells, metabolism, and therapeutic significance.癌症干细胞、新陈代谢及治疗意义。
Tumour Biol. 2016 May;37(5):5735-42. doi: 10.1007/s13277-016-4945-x. Epub 2016 Feb 10.