Depletion of<scp>L</scp>-arginine induces autophagy as a cytoprotective response to endoplasmic reticulum stress in human T lymphocytes

García-Navas, Rósula; Munder, Markus; Mollinedo, Faustino

doi:10.4161/auto.21315

Cited by 75 publications

(56 citation statements)

References 65 publications

(69 reference statements)

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“…Resulting from translational downregulation of the z-chain peptide, the principal signal-transduction element [85], this contributes to impaired proliferation and decreased cytokine production accompanied by autophagy to prevent the onset of apoptosis [84]. Indeed, CD3 z is more profoundly decreased in tumor-infiltrating than in circulating T lymphocytes [17,85], partially explaining their compromised antitumor efficacy as a result of nutrient starvation.…”

Section: Arginine and The Complex Interplay With The Tumor Microenvirmentioning

confidence: 99%

“…Hence, under certain conditions, T cells have evolved strategies to conquer acute arginine depletion. Replenishment of arginine drives T lymphocytes to proliferate again and they recover their normal cell cycle profile, whereby autophagy is inhibited and no longer required [84,86].…”

Section: Arginine and The Complex Interplay With The Tumor Microenvirmentioning

confidence: 99%

“…Under low arginine conditions, T cells have decreased numbers of T-cell receptors on the cell membrane and show an endoplasmic reticulum stress response (through ERN1 signaling) as well as cell cycle arrest at G 0 /G 1 [84]. Resulting from translational downregulation of the z-chain peptide, the principal signal-transduction element [85], this contributes to impaired proliferation and decreased cytokine production accompanied by autophagy to prevent the onset of apoptosis [84].…”

Section: Arginine and The Complex Interplay With The Tumor Microenvirmentioning

confidence: 99%

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Arginine-Depleting Enzymes – An Increasingly Recognized Treatment Strategy for Therapy-Refractory Malignancies

Riess

Shokraie

Classen

et al. 2018

Cell Physiol Biochem

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Arginine auxotrophy occurs in certain tumor types and is usually caused by the silencing of argininosuccinate synthetase 1 or arginine lyase genes. Such tumors are often associated with an intrinsic chemoresistance and thus a poor prognosis. Arginine auxotrophy however renders these tumors vulnerable to treatment with arginine-degrading enzymes. Among the most frequently applied arginine-degrading agents are bacterial arginine deiminases (ADI). The anti-cancerous effects of ADI derived from different bacteria were extensively studied in numerous preclinical cell culture and xenograft models. Mycoplasma-derived ADI-PEG20 is most commonly used and is currently under clinical investigation as a single agent therapeutic as well as in combination with different antineoplastic compounds. Mechanistically, ADI is capable of reducing metabolic activity in tumor cells, contributing to autophagy, senescence and apoptosis in arginine auxotrophic cells. Although clinical trials are promising, the resistance development upon initial treatment response is an increasing challenge. Furthermore, interference of ADI with the tumor microenvironment is poorly understood. In the present review, we outline recent experimental ADI-based treatment approaches and their translation into the clinic. Furthermore, we summarize new insights into the molecular mechanisms underlying the anti-cancer effects of ADI that might facilitate the refinement of ADI-based combination therapy approaches.

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Section: Arginine and The Complex Interplay With The Tumor Microenvirmentioning

confidence: 99%

Section: Arginine and The Complex Interplay With The Tumor Microenvirmentioning

confidence: 99%

Section: Arginine and The Complex Interplay With The Tumor Microenvirmentioning

confidence: 99%

See 1 more Smart Citation

Arginine-Depleting Enzymes – An Increasingly Recognized Treatment Strategy for Therapy-Refractory Malignancies

Riess

Shokraie

Classen

et al. 2018

Cell Physiol Biochem

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“…The UPR protects the cells through mechanisms involving increased protein folding, the degradation of misfolded proteins, and the inhibition of global protein synthesis, or induces cell death under conditions of prolonged ER stress (Zinszner et al 1998;Ron and Walter 2007). It is well known that nutrient depletion (such as glucose and amino acids) leads to autophagy by activation of ER stress signaling (Garcia-Navas et al 2012;Yang et al 2014). Recent study shows that ER stress signaling can also be activated by toxic reagents, such as drugs and carcinogens (Chen et al 2014).…”

Section: Discussionmentioning

confidence: 97%

Excessive l-cysteine induces vacuole-like cell death by activating endoplasmic reticulum stress and mitogen-activated protein kinase signaling in intestinal porcine epithelial cells

Dai

et al. 2015

Amino Acids

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High intake of dietary cysteine is extremely toxic to animals and the underlying mechanism remains largely unknown. This study was conducted to test the hypothesis that excessive L-cysteine induces cell death by activating endoplasmic reticulum (ER) stress and mitogen-activated protein kinase (MAPK) signaling in intestinal porcine epithelial cells. Jejunal enterocytes were cultured in the presence of 0-10 mmol/L L-cysteine. Cell viability, morphologic alterations, mRNA levels for genes involved in ER stress, protein abundances for glucose-regulated protein 78, C/EBP homologous protein (CHOP), alpha subunit of eukaryotic initiation factor-2 (eIF2α), extracellular signal-regulated kinase (ERK1/2), p38 MAPK, and c-Jun N-terminal protein kinase (JNK1/2) were determined. The results showed that L-cysteine (5-10 mmol/L) reduced cell viability (P < 0.05) and led to vacuole-like cell death in intestinal porcine epithelial cells. These adverse effects of L-cysteine were not affected by the autophagy inhibitor 3-methyladenine. The protein abundances for CHOP, phosphorylated (p)-eIF2α, p-JNK1/2, p-p38 MAPK, and the spliced form of XBP-1 mRNA were enhanced (P < 0.05), whereas those for p-ERK1/2 were reduced (P < 0.05). Collectively, excessive L-cysteine induces vacuole-like cell death via the activation of ER stress and MAPK signaling in small intestinal epithelial cells. These signaling pathways may be potential targets for developing effective strategies to prevent the toxicity of dietary cysteine.

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“…While the data clearly shows that leucine is essential for mTORC1 activity in immune cells, the evidence for a similar sensitivity to arginine is lacking. Activated T cells do not seem to be acutely sensitive to arginine deprivation as is the case for leucine [57,70]. Interestingly, effector T cells upregulate Slc7a5 mediated amino acid transport in response to arginine deprivation [71].…”

Section: Amino Acids and Mtorc1mentioning

confidence: 97%

Nutrient sensing, signal transduction and immune responses

Walls

Sinclair

Finlay

2016

Seminars in Immunology

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Most cells in the body have a constant supply of nutrients, which are required to sustain cellular metabolism and functions. In contrast, cells of the immune system can encounter conditions with a limited nutrient supply during the course of an immune response. Cells of the immune system frequently operate in complex nutrient restricted microenvironments such as tumour or inflammatory sites. The concentrations of key nutrients such as glucose and certain amino acids, can be low at these sites, and this can have an impact upon immune cell function. Nutrient sufficiency is important to supply the metabolic and biosynthetic pathways of immune cells. In addition nutrients can also act as important cues that influence immunological signalling pathways to affect the function of immune cells. This review will describe the various nutrient sensing signalling pathways and discuss the evidence that nutrients are critical signals that shape immune responses.

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Depletion ofL-arginine induces autophagy as a cytoprotective response to endoplasmic reticulum stress in human T lymphocytes

Cited by 75 publications

References 65 publications

Arginine-Depleting Enzymes – An Increasingly Recognized Treatment Strategy for Therapy-Refractory Malignancies

Arginine-Depleting Enzymes – An Increasingly Recognized Treatment Strategy for Therapy-Refractory Malignancies

Excessive l-cysteine induces vacuole-like cell death by activating endoplasmic reticulum stress and mitogen-activated protein kinase signaling in intestinal porcine epithelial cells

Nutrient sensing, signal transduction and immune responses

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