Published online Nov 26, 2020. doi: 10.4252/wjsc.v12.i11.1410
Peer-review started: July 10, 2020
First decision: August 9, 2020
Revised: August 19, 2020
Accepted: September 25, 2020
Article in press: September 25, 2020
Published online: November 26, 2020
Processing time: 139 Days and 0.8 Hours
Redox metabolism modulates stem cell and cancer stem cell (CSC) functionality in different model systems, regardless of their dominant metabolic phenotype. In fact, CSCs from several cancer types show increased glutathione content and associated enzymes.
Identification of metabolic vulnerabilities of highly aggressive CSCs can lead to the development of more effective treatment strategies for pancreatic cancer.
The present study aimed to determine the importance of glutathione metabolism for pancreatic CSCs as compared to their differentiated counterparts.
Comparisons between CSCs and non-CSCs in primary pancreatic cancer cells of patient-derived xenografts were carried out by culturing in adherent or CSC-enriching sphere conditions and confirmed by CD133 staining by flow cytometry. Gene expression analyses were performed by RNAseq or real-time PCR. Public TCGA and GTEx RNAseq data from pancreatic cancer vs normal tissue samples were analyzed using the webserver GEPIA2. Staining for measurement of glutathione (monochlorobimane), cell cycle (propidium iodide) or apoptosis (Annexin-V) were determined by fluorimetry or flow cytometry. Pharmacological glutathione depletion was achieved with inhibitors of glutathione synthesis (buthionine-sulfoximine) and recycling (6-Aminonicotinamide). Self-renewal was assessed by sphere formation assay and response to gemcitabine treatment was used as a readout for chemoresistance.
Several glutathione metabolism genes were upregulated in pancreatic CSCs, and their expression correlates with a stemness signature and predicts survival in clinical samples. Increased glutathione concentration in CSCs promotes viability, cell cycle progression and pluripotency gene expression. Inhibition of glutathione synthesis or recycling impairs CSC functionalities such as self-renewal and chemoresistance.
Our data suggest that pancreatic CSCs depend on glutathione metabolism. Pharmacological targeting of this pathway showed that high GSH (glutathione in its reduced form) content is essential to maintain CSC functionality in terms of self-renewal and chemoresistance.
Our data demonstrate a targetable metabolic vulnerability of this aggressive subpopulation of cancer cells, which could be exploited for therapeutic purposes.