Autophagy in cancer: The cornerstone during glutamine deprivation

Fares, Hamza M.; Lyu, Xiaodan; Xu, Xiangdong; Dong, Renchao; Ding, Muyao; Mi, Shichao; Wang, Yifan; Li, Xue; Yuan, Shengtao; Sun, Li

doi:10.1016/j.ejphar.2021.174723

Cited by 9 publications

(10 citation statements)

References 106 publications

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“…As glutamine starvation has been reported to induce autophagy as a survival mechanism ( 20 ) and that V-ATPase inhibition blocks autophagy ( 16 ), we analyzed autophagy. In our model, glutamine deprivation led to a decrease in LC3-II protein levels, indicating autophagy induction.…”

Section: Resultsmentioning

confidence: 99%

A metabolic shift toward glycolysis enables cancer cells to maintain survival upon concomitant glutamine deprivation and V-ATPase inhibition

et al. 2023

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It is widely known that most cancer cells display an increased reliance on glutaminolysis to sustain proliferation and survival. Combining glutamine deprivation with additional anti-cancer therapies is an intensively investigated approach to increase therapeutic effectiveness. In this study, we examined a combination of glutamine deprivation by starvation or pharmacological tools, with the anti-cancer agent archazolid, an inhibitor of the lysosomal V-ATPase. We show that glutamine deprivation leads to lysosomal acidification and induction of pro-survival autophagy, which could be prevented by archazolid. Surprisingly, a combination of glutamine deprivation with archazolid did not lead to synergistic induction of cell death or reduction in proliferation. Investigating the underlying mechanisms revealed elevated expression and activity of amino acid transporters SLC1A5, SLC38A1 upon starvation, whereas archazolid had no additional effect. Furthermore, we found that the export of lysosomal glutamine derived from exogenous sources plays no role in the phenotype as knock-down of SLC38A7, the lysosomal glutamine exporter, could not increase V-ATPase inhibition-induced cell death or reduce proliferation. Analysis of the cellular metabolic phenotype revealed that glutamine deprivation led to a significant increase in glycolytic activity, indicated by an elevated glycolytic capacity and reserve, when V-ATPase function was inhibited concomitantly. This was confirmed by increased glutamine uptake, augmented lactate production, and an increase in hexokinase activity. Our study, therefore, provides evidence, that glutamine deprivation induces autophagy, which can be prevented by simultaneous inhibition of V-ATPase function. However, this does not lead to a therapeutic benefit, as cells are able to circumvent cell death and growth inhibition by a metabolic shift toward glycolysis.

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Section: Resultsmentioning

confidence: 99%

A metabolic shift toward glycolysis enables cancer cells to maintain survival upon concomitant glutamine deprivation and V-ATPase inhibition

et al. 2023

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“…KRAS and YAP/TAZ induce the aspartate synthase (GOT1) expression, which provides NADPH for the proper maintenance of redox homeostasis and produces NEAAs and TCA cycle intermediates for cell growth and produces NEAAs and TCA cycle intermediates 85,86 . mTORC1 and mTORC2 regulate glutaminolysis by inducing the expression of glutamate dehydrogenase and GS, respectively 87,88 …”

Section: Metabolism In Tumorsmentioning

confidence: 99%

Metabolic insights into tumor pathogenesis: Unveiling pan‐cancer metabolism and the potential of untargeted metabolomics

Wang,

Gao

2023

MedComm – Future Medicine

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Metabolic dysregulation is a hallmark of cancer, underpinning diverse aggressive behaviors such as uncontrolled proliferation, immune evasion, and metastasis. Despite the potential of tumor metabolites as biomarkers, their utility has been hampered by metabolic heterogeneity. Exploring cancer metabolism aims to discern shared metabolic pathways and have a better understanding the metabolic heterogeneity of tumors. This approach offers a holistic view of cancer metabolism, facilitating the identification of multicancer‐relevant metabolic targets and the development of more broadly effective therapeutics. In this review, we present a comprehensive overview of the current landscape of cancer metabolism and its prospective applications in cancer diagnosis and prognosis. We delineate common metabolic aberrations observed across a spectrum of cancer types and elucidate the unique metabolic signatures characterizing the six leading causes of cancer‐related mortality. Furthermore, we survey the utilization of untargeted metabolomics and single‐cell technologies in cancer screening, diagnosis, and prognosis, while also spotlighting available data resources for pan‐cancer metabolomics analyses. Throughout this discussion, we tackle prevailing research challenges and propose strategies aimed at enhancing cancer management. Our objective is to furnish valuable insights that can inform and guide future research endeavors in the dynamic realm of cancer metabolism.

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“…Consequently, it has been observed that genetic mutations affecting autophagic genes promote cellular degeneration [ 103 , 104 ], promote early-age-related phenotypes [ 105 , 106 ], tumor development [ 107 , 108 ], and susceptibility to infections in animals [ 109 , 110 ]. Similarly, mutations of genes related to autophagy are present in several Mendelian diseases in humans such as Rett’s syndrome, Parkinson’s disease, cataracts, several forms of cardiomyopathies, among others [ 111 ].…”

Section: Autophagy and Animal Healthmentioning

confidence: 99%

Antimicrobial peptides with cell-penetrating activity as prophylactic and treatment drugs

2022

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Health is fundamental for the development of individuals and evolution of species. In that sense, for human societies is relevant to understand how the human body has developed molecular strategies to maintain health. In the present review, we summarize diverse evidence that support the role of peptides in this endeavor. Of particular interest to this review are antimicrobial (AMP) and cell-penetrating peptides (CPP). Different experimental evidence indicates that AMP/CPP are able to regulate autophagy, which in turn regulates the immune system response. AMP also assists in the establishment of the microbiota, which in turn is critical for different behavioral and health aspects of humans. Thus, AMP and CPP are multifunctional peptides that regulate two aspects of our bodies that are fundamental to our health: autophagy and microbiota. While it is now clear the multifunctional nature of these peptides, we are still in the early stages of the development of computational strategies aimed to assist experimentalists in identifying selective multifunctional AMP/CPP to control non-healthy conditions. For instance, both AMP and CPP are computationally characterized as amphipatic and cationic, yet none of these features are relevant to differentiate these peptides from non-AMP or non-CPP. This review aims to highlight current knowledge that may facilitate the development of AMP’s design tools for preventing or treating illness.

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Autophagy in cancer: The cornerstone during glutamine deprivation

Cited by 9 publications

References 106 publications

A metabolic shift toward glycolysis enables cancer cells to maintain survival upon concomitant glutamine deprivation and V-ATPase inhibition

A metabolic shift toward glycolysis enables cancer cells to maintain survival upon concomitant glutamine deprivation and V-ATPase inhibition

Metabolic insights into tumor pathogenesis: Unveiling pan‐cancer metabolism and the potential of untargeted metabolomics

Antimicrobial peptides with cell-penetrating activity as prophylactic and treatment drugs

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