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PI3K/AKT/mTOR通路与音猬因子通路共同协作，抑制人类胰腺癌干细胞特性及肿瘤生长。

PI3K/AKT/mTOR and sonic hedgehog pathways cooperate together to inhibit human pancreatic cancer stem cell characteristics and tumor growth.

作者信息

Sharma Narinder, Nanta Rajesh, Sharma Jay, Gunewardena Sumedha, Singh Karan P, Shankar Sharmila, Srivastava Rakesh K

机构信息

Department of Pharmacology, Toxicology and Therapeutics, and Medicine, University of Kansas Medical Center, Kansas City, KS, 66160, USA.

Celprogen Inc. Torrance, CA 90503, USA.

出版信息

Oncotarget. 2015 Oct 13;6(31):32039-60. doi: 10.18632/oncotarget.5055.

DOI:10.18632/oncotarget.5055
PMID:26451606
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4741658/
Abstract

Cancer stem cells (CSCs) play major roles in cancer initiation, progression, and metastasis. It is evident from growing reports that PI3K/Akt/mTOR and Sonic Hedgehog (Shh) signaling pathways are aberrantly reactivated in pancreatic CSCs. Here, we examined the efficacy of combining NVP-LDE-225 (PI3K/mTOR inhibitor) and NVP-BEZ-235 (Smoothened inhibitor) on pancreatic CSCs characteristics, microRNA regulatory network, and tumor growth. NVP-LDE-225 co-operated with NVP-BEZ-235 in inhibiting pancreatic CSC's characteristics and tumor growth in mice by acting at the level of Gli. Combination of NVP-LDE-225 and NVP-BEZ-235 inhibited self-renewal capacity of CSCs by suppressing the expression of pluripotency maintaining factors Nanog, Oct-4, Sox-2 and c-Myc, and transcription of Gli. NVP-LDE-225 co-operated with NVP-BEZ-235 to inhibit Lin28/Let7a/Kras axis in pancreatic CSCs. Furthermore, a superior interaction of these drugs was observed on spheroid formation by pancreatic CSCs isolated from Pankras/p53 mice. The combination of these drugs also showed superior effects on the expression of proteins involved in cell proliferation, survival and apoptosis. In addition, NVP-LDE-225 co-operated with NVP-BEZ-235 in inhibiting EMT through modulation of cadherin, vimentin and transcription factors Snail, Slug and Zeb1. In conclusion, these data suggest that the combined inhibition of PI3K/Akt/mTOR and Shh pathways may be beneficial for the treatment of pancreatic cancer.

摘要

癌症干细胞（CSCs）在癌症的起始、进展和转移过程中发挥着重要作用。越来越多的报道表明，PI3K/Akt/mTOR和音猬因子（Shh）信号通路在胰腺CSCs中异常重新激活。在此，我们研究了NVP-LDE-225（PI3K/mTOR抑制剂）和NVP-BEZ-235（Smoothened抑制剂）联合使用对胰腺CSCs特性、微小RNA调控网络及肿瘤生长的影响。NVP-LDE-225与NVP-BEZ-235协同作用，通过作用于Gli水平来抑制胰腺CSCs的特性及小鼠体内肿瘤的生长。NVP-LDE-225与NVP-BEZ-235联合使用可通过抑制多能性维持因子Nanog、Oct-4、Sox-2和c-Myc的表达以及Gli的转录来抑制CSCs的自我更新能力。NVP-LDE-225与NVP-BEZ-235协同作用，抑制胰腺CSCs中的Lin28/Let7a/Kras轴。此外，从Pankras/p53小鼠分离出的胰腺CSCs在形成球体方面，观察到这两种药物具有更强的相互作用。这两种药物的联合使用对参与细胞增殖、存活和凋亡的蛋白质表达也显示出更强的效果。此外，NVP-LDE-225与NVP-BEZ-235协同作用，通过调节钙黏蛋白、波形蛋白以及转录因子Snail、Slug和Zeb1来抑制上皮-间质转化（EMT）。总之，这些数据表明联合抑制PI3K/Akt/mTOR和Shh信号通路可能对胰腺癌的治疗有益。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/add1/4741658/05f08bb156a5/oncotarget-06-32039-g013.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/add1/4741658/0b18e38639b2/oncotarget-06-32039-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/add1/4741658/f524245d9b50/oncotarget-06-32039-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/add1/4741658/1eedb382a796/oncotarget-06-32039-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/add1/4741658/58fa8f221162/oncotarget-06-32039-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/add1/4741658/62e3e01b3cf9/oncotarget-06-32039-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/add1/4741658/604e5ba9f0c0/oncotarget-06-32039-g012.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/add1/4741658/05f08bb156a5/oncotarget-06-32039-g013.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/add1/4741658/0b18e38639b2/oncotarget-06-32039-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/add1/4741658/f524245d9b50/oncotarget-06-32039-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/add1/4741658/1eedb382a796/oncotarget-06-32039-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/add1/4741658/58fa8f221162/oncotarget-06-32039-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/add1/4741658/62e3e01b3cf9/oncotarget-06-32039-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/add1/4741658/604e5ba9f0c0/oncotarget-06-32039-g012.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/add1/4741658/05f08bb156a5/oncotarget-06-32039-g013.jpg

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本文引用的文献

1
MicroRNA biogenesis pathways in cancer.癌症中的微小RNA生物合成途径。
Nat Rev Cancer. 2015 Jun;15(6):321-33. doi: 10.1038/nrc3932.
2
Lin28B/Let-7 Regulates Expression of Oct4 and Sox2 and Reprograms Oral Squamous Cell Carcinoma Cells to a Stem-like State.Lin28B/Let-7 调控 Oct4 和 Sox2 的表达，并将口腔鳞状细胞癌细胞重编程为干细胞样状态。
Cancer Res. 2015 Jun 15;75(12):2553-65. doi: 10.1158/0008-5472.CAN-14-2215. Epub 2015 Apr 9.
3
Dual inhibition of allosteric mitogen-activated protein kinase (MEK) and phosphatidylinositol 3-kinase (PI3K) oncogenic targets with a bifunctional inhibitor.
Hedgehog and PI3K/Akt/mTOR Signaling Pathways Involvement in Leukemic Malignancies: Crosstalk and Role in Cell Death.
刺猬信号通路和PI3K/Akt/mTOR信号通路在白血病恶性肿瘤中的作用：相互作用及在细胞死亡中的作用
Cells. 2025 Feb 13;14(4):269. doi: 10.3390/cells14040269.
4
Inhibition of the PI3K/AKT/mTOR pathway in pancreatic cancer: is it a worthwhile endeavor?抑制胰腺癌中的PI3K/AKT/mTOR信号通路：这是一项值得努力的尝试吗？
Ther Adv Med Oncol. 2024 Oct 4;16:17588359241284911. doi: 10.1177/17588359241284911. eCollection 2024.
5
Targeted therapy of cancer stem cells: inhibition of mTOR in pre-clinical and clinical research.癌症干细胞的靶向治疗：mTOR 在临床前和临床研究中的抑制作用。
Cell Death Dis. 2024 Sep 30;15(9):696. doi: 10.1038/s41419-024-07077-8.
6
Unraveling the interplay: exploring signaling pathways in pancreatic cancer in the context of pancreatic embryogenesis.揭示相互作用：在胰腺胚胎发生背景下探索胰腺癌中的信号通路。
Front Cell Dev Biol. 2024 Aug 22;12:1461278. doi: 10.3389/fcell.2024.1461278. eCollection 2024.
7
MSI2 regulates NLK-mediated EMT and PI3K/AKT/mTOR pathway to promote pancreatic cancer progression.微星2（MSI2）通过调控Nemo样激酶（NLK）介导的上皮-间质转化（EMT）和磷脂酰肌醇-3激酶（PI3K）/蛋白激酶B（AKT）/哺乳动物雷帕霉素靶蛋白（mTOR）信号通路来促进胰腺癌进展。
Cancer Cell Int. 2024 Aug 3;24(1):273. doi: 10.1186/s12935-024-03444-9.
8
Identified γ-glutamyl cyclotransferase (GGCT) as a novel regulator in the progression and immunotherapy of pancreatic ductal adenocarcinoma through multi-omics analysis and experiments.通过多组学分析和实验，鉴定 γ-谷氨酰环转移酶（GGCT）为胰腺导管腺癌进展和免疫治疗的新调控因子。
J Cancer Res Clin Oncol. 2024 Jun 25;150(6):318. doi: 10.1007/s00432-024-05789-0.
9
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Cells. 2024 Jan 26;13(3):240. doi: 10.3390/cells13030240.
10
The deubiquitinating enzyme USP44 suppresses hepatocellular carcinoma progression by inhibiting Hedgehog signaling and PDL1 expression.去泛素化酶 USP44 通过抑制 Hedgehog 信号通路和 PDL1 表达抑制肝癌进展。
Cell Death Dis. 2023 Dec 14;14(12):830. doi: 10.1038/s41419-023-06358-y.
使用双功能抑制剂对变构丝裂原活化蛋白激酶（MEK）和磷脂酰肌醇3激酶（PI3K）致癌靶点进行双重抑制。
Bioorg Med Chem. 2015 Apr 1;23(7):1386-94. doi: 10.1016/j.bmc.2015.02.053. Epub 2015 Mar 6.
4
Genetic variants in let-7/Lin28 modulate the risk of oral cavity cancer in a Chinese Han population.let-7/Lin28基因变异对中国汉族人群口腔癌风险的影响
Sci Rep. 2014 Dec 11;4:7434. doi: 10.1038/srep07434.
5
Lin28/let-7 axis regulates aerobic glycolysis and cancer progression via PDK1.Lin28/let-7 轴通过 PDK1 调节有氧糖酵解和癌症进展。
Nat Commun. 2014 Oct 10;5:5212. doi: 10.1038/ncomms6212.
6
NVP-BEZ-235 enhances radiosensitization via blockade of the PI3K/mTOR pathway in cisplatin-resistant non-small cell lung carcinoma.NVP-BEZ-235通过阻断顺铂耐药的非小细胞肺癌中的PI3K/mTOR途径增强放射增敏作用。
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7
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Ann Neurosci. 2014 Jan;21(1):28-31. doi: 10.5214/ans.0972.7531.210109.
8
Expression of LIN28 and its regulatory microRNAs in adult adrenocortical cancer.LIN28及其调控性微小RNA在成人肾上腺皮质癌中的表达
Clin Endocrinol (Oxf). 2015 Apr;82(4):481-8. doi: 10.1111/cen.12607. Epub 2014 Nov 3.
9
Mechanisms of disseminated cancer cell dormancy: an awakening field.播散性癌细胞休眠的机制：一个觉醒的领域。
Nat Rev Cancer. 2014 Sep;14(9):611-22. doi: 10.1038/nrc3793. Epub 2014 Aug 14.
10
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Cancer Lett. 2014 Oct 10;353(1):32-40. doi: 10.1016/j.canlet.2014.06.021. Epub 2014 Jul 19.