Accelerated lipid catabolism and autophagy are cancer survival mechanisms under inhibited glutaminolysis

Halama, Anna; Kuliński, Michał; Dib, Shaima S.; Zaghlool, Shaza B.; Siveen, Kodappully Sivaraman; Iskandarani, Ahmad; Zierer, Jonas; Prabhu, Kirti S.; Satheesh, Noothan Jyothi; Bhagwat, Aditya; Uddin, Shahab; Kastenmüller, Gabi; Elemento, Olivier; Gross, Steven S.; Suhre, Karsten

doi:10.1016/j.canlet.2018.05.017

Cited by 62 publications

(41 citation statements)

References 50 publications

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“…Consequently, it is feasible to suggest that β‐oxidation of lipids, confirmed by CPTII, FBPase, and LXRα/β expression and a reduction in the amount of free triglycerides at day 75, is the source of energy which supports gluconeogenesis and the glucose found in starving conditions. In addition, the AhR pathway activation prediction during starvation, and the results obtained treating the cells with troglitazone, a well‐known gluconeogenesis and β‐oxidation inhibitor , enabled confirmation of a direct involvement of β‐oxidation as alternative energetic source, also highlighted by recently published papers .…”

Section: Discussionmentioning

confidence: 59%

Survival/Adaptation of Bone Marrow-Derived Mesenchymal Stem Cells After Long-Term Starvation Through Selective Processes

et al. 2019

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After in vivo transplantation, mesenchymal stem cells (MSC) face an ischemic microenvironment, characterized by nutrient deprivation and reduced oxygen tension, which reduces their viability and thus their therapeutic potential. Therefore, MSC response to models of in vitro ischemia is of relevance for improving their survival and therapeutic efficacy. The aim of this study was to understand the survival/adaptive response mechanism that MSC use to respond to extreme culture conditions. Specifically, the effect of a long‐term starvation on human bone marrow (hBM)‐derived MSC cultured in a chemically defined medium (fetal bovine serum‐free [SF] and human SF), either in hypoxic or normoxic conditions. We observed that hBM‐MSC that were isolated and cultured in SF medium and subjected to a complete starvation for up to 75 days transiently changed their behavior and phenotype. However, at the end of that period, hBM‐MSC retained their characteristics as determined by their morphology, DNA damage resistance, proliferation kinetic, and differentiation potential. This survival mode involved a quiescent state, confirmed by increased expression of cell cycle regulators p16, p27, and p57 and decreased expression of proliferating cell nuclear antigen (PCNA), Ki‐67, mTOR, and Nanog. In addition, Jak/STAT (STAT6) antiapoptotic activity selected which cells conserved stemness and that supported metabolic, bioenergetic, and scavenging requirements. We also demonstrated that hBM‐MSC exploited an autophagic process which induced lipid β‐oxidation as an alternative energy source. Priming MSC by concomitant starvation and culture in hypoxic conditions to induce their quiescence would be of benefit to increase MSC survival when transplanted in vivo. Stem Cells 2019;37:813–827

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Section: Discussionmentioning

confidence: 59%

Survival/Adaptation of Bone Marrow-Derived Mesenchymal Stem Cells After Long-Term Starvation Through Selective Processes

et al. 2019

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“…7a). Reductions in phospholipids and triacylglycerols coupled with elevations in their downstream catabolites suggested mitophagy 42,43 . Consistent with this, treatment of PC-3M cells with eliglustat increased protein expression of the mitophagy-associated markers LC3B-II ( Fig.…”

Section: Shunting Of Ceramides Into Glycosphingolipids Is Targetablementioning

confidence: 99%

Caveolin-1-mediated sphingolipid oncometabolism underlies a metabolic vulnerability of prostate cancer

et al. 2020

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Plasma and tumor caveolin-1 (Cav-1) are linked with disease progression in prostate cancer. Here we report that metabolomic profiling of longitudinal plasmas from a prospective cohort of 491 active surveillance (AS) participants indicates prominent elevations in plasma sphingolipids in AS progressors that, together with plasma Cav-1, yield a prognostic signature for disease progression. Mechanistic studies of the underlying tumor supportive oncometabolism reveal coordinated activities through which Cav-1 enables rewiring of cancer cell lipid metabolism towards a program of 1) exogenous sphingolipid scavenging independent of cholesterol, 2) increased cancer cell catabolism of sphingomyelins to ceramide derivatives and 3) altered ceramide metabolism that results in increased glycosphingolipid synthesis and efflux of Cav-1-sphingolipid particles containing mitochondrial proteins and lipids. We also demonstrate, using a prostate cancer syngeneic RM-9 mouse model and established cell lines, that this Cav-1-sphingolipid program evidences a metabolic vulnerability that is targetable to induce lethal mitophagy as an anti-tumor therapy.

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“…However, stopping this process is not sufficient to cause cancer death. This is probably due to this pathway being compensated by increased lipid metabolism [154].…”

Section: Cross Talk Between Lipids Glucose and Glutaminementioning

confidence: 99%

Involvement of Metabolic Lipid Mediators in the Regulation of Apoptosis

et al. 2020

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Apoptosis is the physiological mechanism of cell death and can be modulated by endogenous and exogenous factors, including stress and metabolic alterations. Reactive oxygen species (ROS), as well as ROS-dependent lipid peroxidation products (including isoprostanes and reactive aldehydes including 4-hydroxynonenal) are proapoptotic factors. These mediators can activate apoptosis via mitochondrial-, receptor-, or ER stress-dependent pathways. Phospholipid metabolism is also an essential regulator of apoptosis, producing the proapoptotic prostaglandins of the PGD and PGJ series, as well as the antiapoptotic prostaglandins of the PGE series, but also 12-HETE and 20-HETE. The effect of endocannabinoids and phytocannabinoids on apoptosis depends on cell type-specific differences. Cells where cannabinoid receptor type 1 (CB1) is the dominant cannabinoid receptor, as well as cells with high cyclooxygenase (COX) activity, undergo apoptosis after the administration of cannabinoids. In contrast, in cells where CB2 receptors dominate, and cells with low COX activity, cannabinoids act in a cytoprotective manner. Therefore, cell type-specific differences in the pro- and antiapoptotic effects of lipids and their (oxidative) products might reveal new options for differential bioanalysis between normal, functional, and degenerating or malignant cells, and better integrative biomedical treatments of major stress-associated diseases.

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Accelerated lipid catabolism and autophagy are cancer survival mechanisms under inhibited glutaminolysis

Cited by 62 publications

References 50 publications

Survival/Adaptation of Bone Marrow-Derived Mesenchymal Stem Cells After Long-Term Starvation Through Selective Processes

Survival/Adaptation of Bone Marrow-Derived Mesenchymal Stem Cells After Long-Term Starvation Through Selective Processes

Caveolin-1-mediated sphingolipid oncometabolism underlies a metabolic vulnerability of prostate cancer

Involvement of Metabolic Lipid Mediators in the Regulation of Apoptosis

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