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AGC1-mediated Metabolic Reprogramming and Autophagy Sustain Survival of Hepatocellular Carcinoma Cells under Glutamine Deprivation

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Abstract

The dependence of hepatocellular carcinoma (HCC) cells on glutamine suggests the feasibility of targeting glutamine metabolism for therapy. However, drugs inhibiting glutamine uptake and breakdown have not shown promising outcomes. Therefore, investigating the mechanism of glutamine metabolism reprogramming in HCC cells is crucial. We used bioinformatics approaches to investigate the metabolic flux of glutamine in HCC cells and validated it using qRT-PCR and western blotting. HCC cells were cultured in glutamine-deprived medium, and changes in glutamate and ATP levels were monitored. Western blotting was employed to assess the expression of AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) and autophagy-related proteins. The impact of Solute carrier family 25 member 12 (AGC1) on HCC cell proliferation was studied using CCK-8 and colony formation assays. Furthermore, the effects of AGC1 knockdown via siRNA on metabolic reprogramming and energy supply during glutamine deprivation in HCC were explored. During glutamine deprivation, HCC cells sustain cytosolic asparagine synthesis and ATP production through AGC1. Low ATP levels activate AMPK and inhibit mTOR activation, inducing autophagy to rescue HCC cell survival. Knockdown of AGC1 inhibits mitochondrial aspartate output and continuously activates autophagy, rendering HCC cells more sensitive to glutamine deprivation. AGC1 serves as a critical node in the reprogramming of glutamine metabolism and energy supply in HCC cells. This study provides theoretical support for overcoming resistance to drugs targeting glutamine metabolism.

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Data Availability

No datasets were generated or analysed during the current study.

Abbreviations

α-KG :

α-Ketoglutaric acid

Ala :

Alanine

Asn :

Asparagine

ASNS :

Asparagine Synthetase (Glutamine-Hydrolyzing)

Asp :

Aspartate

ATF4 :

Activating Transcription Factor 4

CAD :

Carbamoyl-Phosphate Synthetase 2, Aspartate Transcarbamylase, And Dihydroorotase

Cys :

Cystine

DSS :

Disease Specific Survival

GCLC :

Glutamate-Cysteine Ligase Catalytic Subunit

GCLM :

Glutamate-Cysteine Ligase Modifier Subunit

GFPT1 :

Glutamine–Fructose-6-Phosphate Transaminase 1

GFPT2 :

Glutamine–Fructose-6-Phosphate Transaminase 2

Gln :

Glutamine

Glu :

Glutamate

GLU :

Glucose

Gly :

Glycine

GLS :

Glutaminase

GLS2 :

Glutaminase 2

GLUL :

Glutamate–Ammonia Ligase

GLUD1 :

Glutamate Dehydrogenase 1

GOT1 :

Glutamic–Oxaloacetic Transaminase 1

GOT2 :

Glutamic–Oxaloacetic Transaminase 2

GPT :

Glutamic–Pyruvic Transaminase

GPT2 :

Glutamic–Pyruvic Transaminase 2

GSH :

Glutathione

GSS :

Glutathione Synthetase

Leu :

Leucine

MDH1 :

Malate Dehydrogenase 1

MDH2 :

Malate Dehydrogenase 2

OAA :

Oxaloacetate

OS :

Overall Survival

PFI :

Progress Free Interval

PPAT :

Phosphoribosyl Pyrophosphate Amidotransferase

PSAT1 :

Phosphoserine Aminotransferase 1

Ser :

Serine

SLC1A5/ASCT2 :

Solute Carrier Family 1 Member 5 (neutral amino acid transporter)

SLC7A5 :

Solute Carrier Family 7 Member 5 (amino acid transporter light chain, L system)

SLC7A11 :

Solute Carrier Family 7 Member 11 (anionic amino acid transporter light chain, xc-system)

SLC25A11/OGC :

Solute Carrier Family 25 Member 11 (oxoglutarate carrier)

SLC25A12/AGC1 :

Solute Carrier Family 25 Member 12 (aspartate/glutamate carrier)

SLC25A13/AGC2 :

Solute Carrier Family 25 Member 13 (aspartate/glutamate carrier)

SLC25A22/GC1 :

Solute Carrier Family 25 Member 22 (glutamate carrier)

SLC25A18/GC2 :

Solute Carrier Family 25 Member 18 (glutamate carrier)

UCP2 :

Uncoupling Protein 2

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Funding

This study was supported by the National Natural Science Foundation of China (No. 31972890 to Q.Y.) and the Department of Science and Technology of Jilin Province (No. 20230101139JC to Q.Y.).

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  1. Department of Pathogenobiology, College of Basic Medical Sciences, Jilin University, Changchun, 130021, Jilin Province, China

    Yan Liu, Zeyu Miao & Qing Yang

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Contributions

Y.L. conceived the study. Y.L. wrote the manuscript. Y.L. and Z.M. performed the experiments and prepared the figures. Q.Y. supervised the study and revised the manuscript.

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Correspondence to Qing Yang.

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It is not applicable. This article does not involve any research on human participants and animals conducted by the authors. The expression data of human liver cancer tissues come from the TCGA (https://portal.gdc.cancer.gov/) and the ICGC (https://dcc.icgc.org/), which are publicly available and free of charge.

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Liu, Y., Miao, Z. & Yang, Q. AGC1-mediated Metabolic Reprogramming and Autophagy Sustain Survival of Hepatocellular Carcinoma Cells under Glutamine Deprivation. Cell Biochem Biophys (2024). https://doi.org/10.1007/s12013-024-01311-y

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