Harnessing the Co-vulnerabilities of Amino Acid-Restricted Cancers

Pathria, Gaurav; Ronai, Ze’ev

doi:10.1016/j.cmet.2020.12.009

Cited by 21 publications

(22 citation statements)

References 129 publications

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“…selective targeting of highly proliferative cancer cells [19]. However, owing to rapid signaling and metabolic reprogramming in cancer cells, the prospects for the success of amino acid restriction approaches are unclear.…”

Section: Discussionmentioning

confidence: 99%

Amino acid deprivation induces AKT activation by inducing GCN2/ATF4/REDD1 axis

et al. 2021

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Amino acid availability is sensed by various signaling molecules, including general control nonderepressible 2 (GCN2) and mechanistic target of rapamycin complex 1 (mTORC1). However, it is unclear how these sensors are associated with cancer cell survival under low amino acid availability. In the present study, we investigated AKT activation in non-small cell lung cancer (NSCLC) cells deprived of each one of 20 amino acids. Among the 20 amino acids, deprivation of glutamine, arginine, methionine, and lysine induced AKT activation. AKT activation was induced by GCN2/ATF4/REDD1 axis-mediated mTORC2 activation under amino acid deprivation. In CRISPR-Cas9-mediated REDD1-knockout cells, AKT activation was not induced by amino acid deprivation, indicating that REDD1 plays a major role in AKT activation under amino acid deprivation. Knockout of REDD1 sensitized cells cultured under glutamine deprivation conditions to radiotherapy. Taken together, GCN2/ATF4/REDD1 axis induced by amino acid deprivation promotes cell survival signal, which might be a potential target for cancer therapy.

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Section: Discussionmentioning

confidence: 99%

Amino acid deprivation induces AKT activation by inducing GCN2/ATF4/REDD1 axis

et al. 2021

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“…Below, we provide a thorough discussion on NEAA biosynthesis for subsequently identifying dysregulations in potential targets that can lead to a dependency on extracellular NEAA sources for survival. Upon identification of an AA dependency, there are several targets within AA metabolic pathways that can be selectively targeted to exploit the vulnerability, including AA transporters, synthases, and transaminases that regulate biosynthesis (13,(29)(30)(31). In addition, enzymatic AA depletion therapy is an effective strategy for preferentially targeting cancer cells dependent on a specific AA for maintaining cell proliferation demands (13).…”

Section: Targeting Aas Dependencies In Myeloid Leukemiasmentioning

confidence: 99%

“…Second, it activates the AAR pathway by concomitantly increasing the translation of a subset of mRNAs with upstream ORFs that regulate translation of the downstream main ORF (179,(181)(182)(183). The AAR pathway leads to the upregulation of amino acid transporters, aminoacyl-tRNA synthetases, enzymes involved in the biosynthesis of amino acids, and proteins involved in autophagy (29,(184)(185)(186).…”

Section: Activation Of the Amino Acid Response Pathway (Aar) Can Lead To Nutrient Stress Resistancementioning

confidence: 99%

Amino Acid Metabolic Vulnerabilities in Acute and Chronic Myeloid Leukemias

et al. 2021

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Amino acid (AA) metabolism plays an important role in many cellular processes including energy production, immune function, and purine and pyrimidine synthesis. Cancer cells therefore require increased AA uptake and undergo metabolic reprogramming to satisfy the energy demand associated with their rapid proliferation. Like many other cancers, myeloid leukemias are vulnerable to specific therapeutic strategies targeting metabolic dependencies. Herein, our review provides a comprehensive overview and TCGA data analysis of biosynthetic enzymes required for non-essential AA synthesis and their dysregulation in myeloid leukemias. Furthermore, we discuss the role of the general control nonderepressible 2 (GCN2) and-mammalian target of rapamycin (mTOR) pathways of AA sensing on metabolic vulnerability and drug resistance.

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“…Protein restriction can be achieved in several ways: by reducing the amount of single essential amino acid, by reducing the levels of specific non-essential amino acids, or by reducing the levels of all amino acids [ 15 ]. Reducing specific non-essential amino acids may reduce cellular proliferation, but cancer cells may adapt accordingly [ 16 , 17 ]. A global reduction in amino acid supply results in two major outcomes: 1) a greatly reduced energy intake and 2) a reprogramming of cellular metabolism [ 15 , 17 ].…”

Section: Introductionmentioning

confidence: 99%

“…Reducing specific non-essential amino acids may reduce cellular proliferation, but cancer cells may adapt accordingly [ 16 , 17 ]. A global reduction in amino acid supply results in two major outcomes: 1) a greatly reduced energy intake and 2) a reprogramming of cellular metabolism [ 15 , 17 ]. The first outcome might be the reason why therapeutic approaches using this approach have so far remained largely unrealized in clinical practice [ 18 ].…”

Section: Introductionmentioning

confidence: 99%