Compensatory cross-talk between autophagy and glycolysis regulates senescence and stemness in heterogeneous glioblastoma tumor subpopulations

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dc.contributor.authorMartell, Emma
dc.contributor.authorKuzmychova, Helgi
dc.contributor.authorSubramanian, Senthil K.
dc.contributor.authorKaul, Dr. Esha
dc.contributor.authorChokshi, Chirayu
dc.contributor.authorVenugopal, Chitra
dc.contributor.authorAnderson, Christopher M.
dc.contributor.authorSingh, Sheila
dc.contributor.authorSharif, Tanveer
dc.date.accessioned2023-11-14T17:11:25Z
dc.date.available2023-11-14T17:11:25Z
dc.date.issued2023-07-07
dc.date.updated2023-11-03T09:18:27Z
dc.description.abstractAbstract Despite tremendous research efforts, successful targeting of aberrant tumor metabolism in clinical practice has remained elusive. Tumor heterogeneity and plasticity may play a role in the clinical failure of metabolism-targeting interventions for treating cancer patients. Moreover, compensatory growth-related processes and adaptive responses exhibited by heterogeneous tumor subpopulations to metabolic inhibitors are poorly understood. Here, by using clinically-relevant patient-derived glioblastoma (GBM) cell models, we explore the cross-talk between glycolysis, autophagy, and senescence in maintaining tumor stemness. We found that stem cell-like GBM tumor subpopulations possessed higher basal levels of glycolytic activity and increased expression of several glycolysis-related enzymes including, GLUT1/SLC2A1, PFKP, ALDOA, GAPDH, ENO1, PKM2, and LDH, compared to their non-stem-like counterparts. Importantly, bioinformatics analysis also revealed that the mRNA expression of glycolytic enzymes positively correlates with stemness markers (CD133/PROM1 and SOX2) in patient GBM tumors. While treatment with glycolysis inhibitors induced senescence in stem cell-like GBM tumor subpopulations, as evidenced by increased β-galactosidase staining and upregulation of the cell cycle regulators p21Waf1/Cip1/CDKN1A and p16INK4A/CDKN2A, these cells maintained their aggressive stemness features and failed to undergo apoptotic cell death. Using various techniques including autophagy flux and EGFP-MAP1LC3B+ puncta formation analysis, we determined that inhibition of glycolysis led to the induction of autophagy in stem cell-like GBM tumor subpopulations, but not in their non-stem-like counterparts. Similarly, blocking autophagy in stem cell-like GBM tumor subpopulations induced senescence-associated growth arrest without hampering stemness capacity or inducing apoptosis while reciprocally upregulating glycolytic activity. Combinatorial treatment of stem cell-like GBM tumor subpopulations with autophagy and glycolysis inhibitors blocked the induction of senescence while drastically impairing their stemness capacity which drove cells towards apoptotic cell death. These findings identify a novel and complex compensatory interplay between glycolysis, autophagy, and senescence that helps maintain stemness in heterogeneous GBM tumor subpopulations and provides a survival advantage during metabolic stress.
dc.identifier.citationActa Neuropathologica Communications. 2023 Jul 07;11(1):110
dc.identifier.doi10.1186/s40478-023-01604-y
dc.identifier.urihttp://hdl.handle.net/1993/37778
dc.language.isoeng
dc.language.rfc3066en
dc.publisherBMC
dc.rightsopen accessen_US
dc.rights.holderCrown
dc.subjectGlioblastoma
dc.subjectTumor heterogeneity
dc.subjectCancer stem cell-like cells
dc.subjectMetabolism
dc.subjectGlycolysis
dc.subjectAutophagy
dc.subjectSenescence
dc.titleCompensatory cross-talk between autophagy and glycolysis regulates senescence and stemness in heterogeneous glioblastoma tumor subpopulations
dc.typeJournal Article
local.author.affiliationRady Faculty of Health Sciences::Max Rady College of Medicine::Department of Pharmacology and Therapeutics
oaire.citation.issue110
oaire.citation.titleActa Neuropathologica Communications
oaire.citation.volume11
project.funder.identifierhttps://doi.org/10.13039/501100000038
project.funder.nameNatural Sciences and Engineering Research Council of Canada
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