Martell 2023 Acta Neuropathol Commun

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Publications in the MiPMap
Martell E, Kuzmychova H, Senthil H, Kaul E, Chokshi CR, Venugopal C, Anderson CM, Singh SK, Sharif T (2023) Compensatory cross-talk between autophagy and glycolysis regulates senescence and stemness in heterogeneous glioblastoma tumor subpopulations.

Β» Acta Neuropathol Commun 11:110. PMID: 37420311 Open Access

Martell Emma, Kuzmychova Helgi, Senthil Harshal, Kaul Esha, Chokshi Chirayu R, Venugopal Chritra, Anderson Christopher M, Singh Sheila K, Sharif Tanveer (2023) Acta Neuropathol Commun

Abstract: 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 Ξ²-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. β€’ Keywords: Autophagy, Cancer stem cell-like cells, Glioblastoma, Glycolysis, Metabolism, Senescence, Tumor heterogeneity β€’ Bioblast editor: Plangger M

Labels: MiParea: Respiration, Patients  Pathology: Aging;senescence, Cancer 

Organism: Human  Tissue;cell: Nervous system  Preparation: Intact cells 

Regulation: Aerobic glycolysis  Coupling state: LEAK, ROUTINE, ET  Pathway: ROX  HRR: Oxygraph-2k 


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