RETRACTED: Fumagillin regulates stemness and malignancies in cancer stem-like cells derived from liver cancer via targeting to MetAP-2 (Retracted article)

被引:6
作者
Zhang, Ke [1 ]
Hu, Jian [1 ]
Zhao, Ziyi [2 ]
机构
[1] Second Peoples Hosp Yibin, Yibin, Sichuan, Peoples R China
[2] Hosp Chengdu Univ Tradit Chinese Med, TCM Regulating Metab Dis Key Lab Sichuan Prov, Chengdu, Sichuan, Peoples R China
基金
中国国家自然科学基金;
关键词
HEPATOCELLULAR-CARCINOMA; AGENT TNP-470; ANGIOGENESIS; GROWTH; INHIBITORS; P53;
D O I
10.1371/journal.pone.0289024
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
BackgroundCancer relapse is associated with the presence of cancer stem-like cells (CSCs), which lead to multidirectional differentiation and unrestricted proliferative replication. Fumagillin, a myocotoxin produced by the saprophytic filamentous fungus Aspergillus fumigatus, has been reported to affect malignant characteristics in hepatocellular cancer cells. However, its exact role in CSCs is still unknown. MethodsCSCs were enriched by culturing cancer cells in serum-free medium. The effects of fumagillin on malignant cell characteristics and mitochondrial function were measured. The regulatory role of fumagillin on methionine aminopeptidase-2 (MetAP-2) was assessed. ResultsWhen it was supplemented in medium, fumagillin treatment inhibited sphere formation and the maintenance of stemness of CSCs without disturbing cell growth. Fumagillin also decreased stemness-related markers and the aldehyde dehydrogenase 1 (ALDH1)-positive proportion, which demonstrated that fumagillin decreases stemness in CSCs. It was also found to inhibit malignant traits in CSCs, including cell proliferation, invasion, and tumor formation, and sensitize CSCs to chemoagents, including sorafenib and doxorubicin, by promoting chemoagent-induced apoptosis. Moreover, fumagillin treatment was found to disturb mitochondrial membrane homeostasis, ATP synthesis and mitochondrial transcriptional activity. In addition, we found that fumagillin decreased MetAP-2 protein levels and exerted anti-CSC effects potentially by regulating MetAP-2. We also found that fumagillin treatment activated p53 and its transcriptional activity and thus caused cell cycle blockade. Moreover, fumagillin treatment significantly decreased tumor formation in nude mice. ConclusionThis work offers evidence for fumagillin as a specific inhibitor of liver cancer CSCs and proposes a novel strategy for cancer therapy.
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页数:16
相关论文
共 27 条
[1]   Conversion surgery after preoperative therapy for advanced hepatocellular carcinoma in the era of molecular targeted therapy and immune checkpoint inhibitors [J].
Arita, Junichi ;
Ichida, Akihiko ;
Nagata, Rihito ;
Mihara, Yuichiro ;
Kawaguchi, Yoshikuni ;
Ishizawa, Takeaki ;
Akamatsu, Nobuhisa ;
Kaneko, Junichi ;
Hasegawa, Kiyoshi .
JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES, 2022, 29 (07) :732-740
[2]   Targeting cancer stem cell propagation with palbociclib, a CDK4/6 inhibitor: Telomerase drives tumor cell heterogeneity [J].
Bonuccelli, Gloria ;
Peiris-Pages, Maria ;
Ozsvari, Bela ;
Martinez-Outschoorn, Ubaldo E. ;
Sotgia, Federica ;
Lisanti, Michael P. .
ONCOTARGET, 2017, 8 (06) :9868-9884
[3]   Methionine aminopeptidases and angiogenesis [J].
Bradshaw, RA ;
Yi, E .
PROTEASES IN BIOLOGY AND MEDICINE, 2002, 38 :65-78
[4]   TNP-470 (AGM-1470): Mechanisms of action and early clinical development [J].
Castronovo, V ;
Belotti, D .
EUROPEAN JOURNAL OF CANCER, 1996, 32A (14) :2520-2527
[5]   A Perspective on Cancer Cell Metastasis [J].
Chaffer, Christine L. ;
Weinberg, Robert A. .
SCIENCE, 2011, 331 (6024) :1559-1564
[6]   The protease-inhibitor SerpinB3 as a critical modulator of the stem-like subset in human cholangiocarcinoma [J].
Correnti, Margherita ;
Cappon, Andrea ;
Pastore, Mirella ;
Piombanti, Benedetta ;
Lori, Giulia ;
Oliveira, Douglas V. P. N. ;
Munoz-Garrido, Patricia ;
Lewinska, Monika ;
Andersen, Jesper B. ;
Coulouarn, Cedric ;
Sulpice, Laurent ;
Neia, Caterina Peraldo ;
Cavalloni, Giuliana ;
Quarta, Santina ;
Biasiolo, Alessandra ;
Fassan, Matteo ;
Ramazzotti, Matteo ;
Parri, Matteo ;
Recalcati, Stefania ;
Tommaso, Luca ;
Campani, Claudia ;
Invernizzi, Pietro ;
Torzilli, Guido ;
Marra, Fabio ;
Pontisso, Patrizia ;
Raggi, Chiara .
LIVER INTERNATIONAL, 2022, 42 (01) :233-248
[7]   Cancer stem cells (CSCs): metabolic strategies for their identification and eradication [J].
de Francesco, Ernestina M. ;
Sotgia, Federica ;
Lisanti, Michael P. .
BIOCHEMICAL JOURNAL, 2018, 475 :1611-1634
[8]  
Dubbelboer IR, 2014, THER DELIV, V5, P447, DOI [10.4155/TDE.14.11, 10.4155/tde.14.11]
[9]  
EBLE TE, 1951, ANTIBIOT CHEMOTHER, V1, P54
[10]   Hepatocellular carcinoma: Epidemiology and molecular carcinogenesis [J].
El-Serag, Hashem B. ;
Rudolph, Lenhard .
GASTROENTEROLOGY, 2007, 132 (07) :2557-2576