Autophagy mediates glucose starvation-induced glioblastoma cell quiescence and chemoresistance through coordinating cell metabolism, cell cycle, and survival

Abstract

Metabolic reprogramming is pivotal to sustain cancer growth and progression. As such dietary restriction therapy represents a promising approach to starve and treat cancers. Nonetheless, tumors are dynamic and heterogeneous populations of cells with metabolic activities modulated by spatial and temporal contexts. Autophagy is a major pathway controlling cell metabolism. It can downregulate cell metabolism, leading to cancer cell quiescence, survival, and chemoresistance. To understand treatment dynamics and provide rationales for better future therapeutic strategies, we investigated whether and how autophagy is involved in the chemo-cytotoxicity and -resistance using two commonly used human glioblastoma (GBM) cell lines U87 and U251 together with primary cancer cells from the GBM patients. Our results suggest that autophagy mediates chemoresistance through reprogramming cancer cell metabolism and promoting quiescence and survival. Further unbiased transcriptome profiling identified a number of clinically relevant pathways and genes, strongly correlated with TCGA data. Our analyses have not only reported many well-known tumor players, but also uncovered a number of genes that were not previously implicated in cancers and/or GBM. The known functions of these genes are highly suggestive. It would be of high interest to investigate their potential involvement in GBM tumorigenesis, progression, and/or drug resistance. Taken together, our results suggest that autophagy inhibition could be a viable approach to aid GBM chemotherapy and combat drug resistance.

Transcriptomic Profiling of 3D Glioblastoma Tumoroids for the Identification of Mechanisms Involved in Anticancer Drug Resistance

“…The elevated rates of glucose uptake and metabolism to sustain their rapid growth combined with nutrient deprivation in glioblastoma spheroids may cause autophagy enhancement and the transition of cells to a quiescent state (37) and promote survival, and as such constitutes a vital mechanism of drug resistance (38). Wang et al demonstrated that upon glucose starvation, while the majority of cancer cells perished due to chemotherapeutic cytotoxicity, subsets of cancer cells can up-regulate their autophagic activity, enter quiescence, and acquire survival advantage and ultimately chemoresistance (39).…”

Dissecting pharmacological effects of chloroquine in cancer treatment: interference with inflammatory signaling pathways

“…182 Several properties of CSC affect the impact of CQ on tumors. 184 These quiescent cells rely on autophagy. 183 During tumor growth, rapidly dividing cells that rely on glycolysis produce lactate.…”

“…This, in turn, generates an acidic microenvironment that when combined with hypoxia leads to the development of quiescent cancer cell clones that share properties with stem cells. 184 These quiescent cells rely on autophagy. 185 Through autophagy, cancer cells and especially cancer stem-like cell clones increase their capacity for material turnover and efflux of cancer drugs.…”

Tumors Responsive to Autophagy-Inhibition: Identification and Biomarkers

“…Glioblastoma (GBM) is the most malignant form of glioma and autophagy activation results in resistance to temozolomide [ 23 , 38 ], suggesting that autophagy targeting in combination with conventional therapy may have beneficial effects on therapy. A significant population of glioblastoma expresses a truncated EGFR receptor, epidermal growth factor receptor variant III (EGFRvIII), which is associated with increased hypoxia tolerance, radio- and chemoresistance and pro-survival [ 39 ].…”