Martell 2023 Acta Neuropathol Commun: Difference between revisions
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|title=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. https://doi.org/10.1186/s40478-023-01604-y | |title=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. https://doi.org/10.1186/s40478-023-01604-y | ||
|info=Acta Neuropathol Commun 11:110. [https://pubmed.ncbi.nlm.nih.gov/37420311 PMID: 37420311 Open Access] | |info=Acta Neuropathol Commun 11:110. [https://pubmed.ncbi.nlm.nih.gov/37420311 PMID: 37420311 Open Access] | ||
|authors=Martell | |authors=Martell Emma, Kuzmychova Helgi, Senthil Harshal, Kaul Esha, Chokshi Chirayu R, Venugopal Chritra, Anderson Christopher M, Singh Sheila K, Sharif Tanveer | ||
|year=2023 | |year=2023 | ||
|journal=Acta Neuropathol Commun | |journal=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 ฮฒ-galactosidase staining and upregulation of the cell cycle regulators | |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 ฮฒ-galactosidase staining and upregulation of the cell cycle regulators p21<sup>Waf1/Cip1</sup>/CDKN1A and p16<sup>INK4A</sup>/CDKN2A, these cells maintained their aggressive stemness features and failed to undergo apoptotic cell death. Using various techniques including autophagy flux and EGFP-MAP1LC3B<sup>+</sup> 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. | ||
|keywords=Autophagy, Cancer stem cell-like cells, Glioblastoma, Glycolysis, Metabolism, Senescence, Tumor heterogeneity | |keywords=Autophagy, Cancer stem cell-like cells, Glioblastoma, Glycolysis, Metabolism, Senescence, Tumor heterogeneity | ||
|editor=[[Plangger M]] | |editor=[[Plangger M]] | ||
}} | }} | ||
{{Labeling | {{Labeling | ||
|area=Respiration | |area=Respiration, Patients | ||
|diseases=Aging;senescence, Cancer | |||
|organism=Human | |||
|tissues=Nervous system | |||
|preparations=Intact cells | |||
|topics=Aerobic glycolysis | |||
|couplingstates=LEAK, ROUTINE, ET | |||
|pathways=ROX | |||
|instruments=Oxygraph-2k | |instruments=Oxygraph-2k | ||
|additional=2023-07 | |additional=2023-07 | ||
}} | }} |
Latest revision as of 15:32, 11 July 2023
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. https://doi.org/10.1186/s40478-023-01604-y |
ยป 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 ฮฒ-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. โข Keywords: Autophagy, Cancer stem cell-like cells, Glioblastoma, Glycolysis, Metabolism, Senescence, Tumor heterogeneity โข 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
2023-07