Dietary restriction of cysteine and methionine sensitizes gliomas to ferroptosis and induces alterations in energetic metabolism

Upadhyayula, Pavan S.; Higgins, Dominique; Mela, Angeliki; Banu, Matei; Dovas, Athanassios; Zandkarimi, Fereshteh; Patel, Purvi; Mahajan, Aayushi; Humala, Nelson; Nguyen, Trang; Chaudhary, Kunal; Liao, Lillian; Argenziano, Michael; Sudhakar, Tejaswi; Sperring, Colin; Shapiro, Benjamin L.; Ahmed, Eman R.; Kinslow, Connor J.; Ye, Ling F.; Siegelin, Markus D.; Cheng, Simon K.; Soni, Rajesh Kumar; Bruce, Jeffrey N.; Stockwell, Brent R.; Canoll, Peter

doi:10.1038/s41467-023-36630-w

Cited by 70 publications

(27 citation statements)

References 48 publications

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“…Gene expression analysis by qRT-qPCR confirmed that cystine deprivation led to the upregulation of targets associated with a ferroptotic response, especially CHAC1, PTGS2, ATF4, and the cystine transporter SLC7A11 (Figure 2a) (Upadhyayula et al, 2023). Next, we sought to understand whether the behavior of MIT/TFE factors in melanoma was altered upon induction of ferroptosis and whether their canonical target genes involved in lysosomal biogenesis would be affected.…”

Section: E T T E R T O T H E E D I T O R Tfe3 Promotes Ferroptosis In...mentioning

confidence: 98%

TFE3 promotes ferroptosis in melanoma

Dias,

Louphrasitthiphol,

Goding

2023

Pigment Cell Melanoma Res

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Section: E T T E R T O T H E E D I T O R Tfe3 Promotes Ferroptosis In...mentioning

confidence: 98%

TFE3 promotes ferroptosis in melanoma

Dias,

Louphrasitthiphol,

Goding

2023

Pigment Cell Melanoma Res

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“…a) Left: Schematic of in vivo head-fixed two-photon imaging with simultaneous whisker stimulation. Right: Schematic of tumor injection placement (yellow marker) with respect to somatosensory cortex (green area, modified from Kirkcaldie et al 72 ).…”

Section: Resultsmentioning

confidence: 99%

“…Alterations in mTOR signaling have been implicated in a variety of neurological diseases with pathological mechanisms relating to mTOR’s critical role in local protein synthesis, dendritic spine morphogenesis and synaptic plasticity 72–74 . Inhibiting mTOR can reduce seizures in animal models of TSC-related epilepsy 75,76 and can reverse TSC-associated alterations in synaptic plasticity with improvements in cognitive deficits 77 .…”

Section: Discussionmentioning

confidence: 99%

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Glioma-Induced Alterations in Excitatory Neurons are Reversed by mTOR Inhibition

Goldberg,

Dovas,

Torres

et al. 2024

Preprint

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Gliomas are highly aggressive brain tumors characterized by poor prognosis and composed of diffusely infiltrating tumor cells that intermingle with non-neoplastic cells in the tumor microenvironment, including neurons. Neurons are increasingly appreciated as important reactive components of the glioma microenvironment, due to their role in causing hallmark glioma symptoms, such as cognitive deficits and seizures, as well as their potential ability to drive glioma progression. Separately, mTOR signaling has been shown to have pleiotropic effects in the brain tumor microenvironment, including regulation of neuronal hyperexcitability. However, the local cellular-level effects of mTOR inhibition on glioma-induced neuronal alterations are not well understood. Here we employed neuron-specific profiling of ribosome-bound mRNA via "RiboTag", morphometric analysis of dendritic spines, and in vivo calcium imaging, along with pharmacological mTOR inhibition to investigate the impact of glioma burden and mTOR inhibition on these neuronal alterations. The RiboTag analysis of tumor-associated excitatory neurons showed a downregulation of transcripts encoding excitatory and inhibitory postsynaptic proteins and dendritic spine development, and an upregulation of transcripts encoding cytoskeletal proteins involved in dendritic spine turnover. Light and electron microscopy of tumor-associated excitatory neurons demonstrated marked decreases in dendritic spine density. In vivo two-photon calcium imaging in tumor-associated excitatory neurons revealed progressive alterations in neuronal activity, both at the population and single-neuron level, throughout tumor growth. This in vivo calcium imaging also revealed altered stimulus-evoked somatic calcium events, with changes in event rate, size, and temporal alignment to stimulus, which was most pronounced in neurons with high-tumor burden. A single acute dose of AZD8055, a combined mTORC1/2 inhibitor, reversed the glioma-induced alterations on the excitatory neurons, including the alterations in ribosome-bound transcripts, dendritic spine density, and stimulus evoked responses seen by calcium imaging. These results point to mTOR-driven pathological plasticity in neurons at the infiltrative margin of glioma - manifested by alterations in ribosome-bound mRNA, dendritic spine density, and stimulus-evoked neuronal activity. Collectively, our work identifies the pathological changes that tumor-associated excitatory neurons experience as both hyperlocal and reversible under the influence of mTOR inhibition, providing a foundation for developing therapies targeting neuronal signaling in glioma.

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“…In this case, Met restriction can reduce Cys and GSH (Glu-Cys-Gly) levels, which may lead to the accumulation of cytotoxic concentrations of ROS in cancer cells. Accordingly, evidence has suggested that Cys supplementation can reduce the anticancer activity of Met restriction [131,132], and many studies have restricted or eliminated Cys in the diet to increase the anticancer activity of this Met restriction [26,27,34,40,111,113,[120][121][122]133]. It has been proposed that cancer cells are more vulnerable than normal cells to Met restriction because cancer cells may be unable to recycle Met from homocysteine (HCys) or SAM through the Met salvage pathways [24].…”

Section: Orillion Et Al 2018 [34]mentioning

confidence: 99%

Dietary Manipulation of Amino Acids for Cancer Therapy

Jiménez-Alonso

López‐Lázaro

2023

Nutrients

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Cancer cells cannot proliferate and survive unless they obtain sufficient levels of the 20 proteinogenic amino acids (AAs). Unlike normal cells, cancer cells have genetic and metabolic alterations that may limit their capacity to obtain adequate levels of the 20 AAs in challenging metabolic environments. However, since normal diets provide all AAs at relatively constant levels and ratios, these potentially lethal genetic and metabolic defects are eventually harmless to cancer cells. If we temporarily replace the normal diet of cancer patients with artificial diets in which the levels of specific AAs are manipulated, cancer cells may be unable to proliferate and survive. This article reviews in vivo studies that have evaluated the antitumor activity of diets restricted in or supplemented with the 20 proteinogenic AAs, individually and in combination. It also reviews our recent studies that show that manipulating the levels of several AAs simultaneously can lead to marked survival improvements in mice with metastatic cancers.

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Dietary restriction of cysteine and methionine sensitizes gliomas to ferroptosis and induces alterations in energetic metabolism

Cited by 70 publications

References 48 publications

TFE3 promotes ferroptosis in melanoma

TFE3 promotes ferroptosis in melanoma

Glioma-Induced Alterations in Excitatory Neurons are Reversed by mTOR Inhibition

Dietary Manipulation of Amino Acids for Cancer Therapy

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