Metformin inhibits cell proliferation, migration and invasion by attenuating CSC function mediated by deregulating miRNAs in pancreatic cancer cells
Bin Bao,Zhiwei Wang,Shadan Ali,Aamir Ahmad,Asfar S. Azmi,Sanila H. Sarkar,Sanjeev Banerjee,Dejuan Kong,Yiwei Li,Shivam Thakur,Fazlul H. Sarkar +10 more
TLDR
It is found that metformin significantly decreased cell survival, clonogenicity, wound-healing capacity, sphere-forming capacity (pancreatospheres), and increased disintegration of pancreatospheres in both gemcitabine-sensitive and gemcitABine-resistant pancreatic cancer cells.Abstract:
Pancreatic cancer is the fourth leading cause of cancer-related deaths in the United States, which is, in part, due to intrinsic (de novo) and extrinsic (acquired) resistance to conventional therapeutics, suggesting that innovative treatment strategies are required for overcoming therapeutic resistance to improve overall survival of patients. Oral administration of metformin in patients with diabetes mellitus has been reported to be associated with reduced risk of pancreatic cancer and that metformin has been reported to kill cancer stem cells (CSC); however, the exact molecular mechanism(s) has not been fully elucidated. In the current study, we examined the effect of metformin on cell proliferation, cell migration and invasion, and self-renewal capacity of CSCs and further assessed the expression of CSC marker genes and microRNAs (miRNA) in human pancreatic cancer cells. We found that metformin significantly decreased cell survival, clonogenicity, wound-healing capacity, sphere-forming capacity (pancreatospheres), and increased disintegration of pancreatospheres in both gemcitabine-sensitive and gemcitabine-resistant pancreatic cancer cells. Metformin also decreased the expression of CSC markers,CD44, EpCAM,EZH2, Notch-1, Nanog and Oct4, and caused reexpression of miRNAs (let-7a,let-7b, miR-26a, miR-101, miR-200b, and miR-200c) that are typically lost in pancreatic cancer and especially in pancreatospheres. We also found that reexpression of miR-26a by transfection led to decreased expression of EZH2 and EpCAM in pancreatic cancer cells. These results clearly suggest that the biologic effects of metformin are mediated through reexpression of miRNAs and decreased expression of CSC-specific genes, suggesting that metformin could be useful for overcoming therapeutic resistance of pancreatic cancer cells.read more
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Cancer metabolism: a therapeutic perspective
Ubaldo E. Martinez-Outschoorn,Maria Peiris-Pagès,Richard G. Pestell,Federica Sotgia,Federica Sotgia,Michael P. Lisanti +5 more
TL;DR: How cancer cells reprogramme their metabolism and that of other cells within the tumour microenvironment in order to survive and propagate, thus driving disease progression is discussed; in particular, potential metabolic vulnerabilities that might be targeted therapeutically are highlighted.
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Metformin inhibits the inflammatory response associated with cellular transformation and cancer stem cell growth
TL;DR: Observations suggest that metformin inhibits a signal transduction pathway that results in an inflammatory response that stimulates the inflammatory pathway associated with a wide variety of cancers.
Journal ArticleDOI
Erratum: Cancer metabolism: a therapeutic perspective
Ubaldo E. Martinez-Outschoorn,Maria Peiris-Pagès,Richard G. Pestell,Federica Sotgia,Michael P. Lisanti +4 more
TL;DR: Owing to a typesetting error, the final line of text in Box 3, and the abbreviation lists for Tables 2 and 3 were omitted from the print and the online pdf versions of this article; for Table 3, the abbrevation list was also omitted fromThe online html version.
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James A. McCubrey,Linda S. Steelman,William H. Chappell,Stephen L. Abrams,Richard A. Franklin,Giuseppe Montalto,Melchiorre Cervello,Massimo Libra,Saverio Candido,Grazia Malaponte,Maria Clorinda Mazzarino,Paolo Fagone,Ferdinando Nicoletti,Jörg Bäsecke,Sanja Mijatović,Danijela Maksimović-Ivanić,Michele Milella,Agostino Tafuri,Francesca Chiarini,Camilla Evangelisti,Lucio Cocco,Alberto M. Martelli +21 more
TL;DR: How cancers can become insensitive to various inhibitors and potential strategies to overcome this resistance are discussed.
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Hypoxia-inducing factors as master regulators of stemness properties and altered metabolism of cancer- and metastasis-initiating cells.
TL;DR: The targeting of HIF signalling network and altered metabolic pathways represents new promising strategies to eradicate the total mass of cancer cells and improve the efficacy of current therapies against aggressive and metastatic cancers and prevent disease relapse.
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