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

Acta Neuropathologica Communications

Research

Chirayu R. Chokshi¹  Sheila K. Singh²  Harshal Senthil³  Helgi Kuzmychova³  Emma Martell⁴  Tanveer Sharif⁴  Christopher M. Anderson⁵  Chitra Venugopal⁶  Esha Kaul⁷ 

[1] Department of Biochemistry, McMaster University, Hamilton, ON, Canada;Department of Biochemistry, McMaster University, Hamilton, ON, Canada;Department of Surgery, McMaster University, Hamilton, ON, Canada;Department of Pathology, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada;Department of Pathology, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada;Department of Human Anatomy and Cell Science, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada;Department of Pharmacology and Therapeutics, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada;Neuroscience Research Program, Kleysen Institute for Advanced Medicine, Health Sciences Centre, Winnipeg, MB, Canada;Department of Surgery, McMaster University, Hamilton, ON, Canada;Faculty of Science, University of Manitoba, Winnipeg, MB, Canada;

关键词: Glioblastoma;    Tumor heterogeneity;    Cancer stem cell-like cells;    Metabolism;    Glycolysis;    Autophagy;    Senescence;   

DOI  :  10.1186/s40478-023-01604-y

 received in 2023-04-04, accepted in 2023-06-16,  发布年份 2023

来源: Springer

【 摘 要 】

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.

【 授权许可】

CC BY   
© Crown 2023

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