Related Experiment Video

Updated: May 16, 2026

Cell-Based Drug Screening for Inhibitors of Autophagy Related 4B Cysteine Peptidase
09:51

Cell-Based Drug Screening for Inhibitors of Autophagy Related 4B Cysteine Peptidase

Published on: June 30, 2023

ATF4 regulates MYC-mediated neuroblastoma cell death upon glutamine deprivation

Guoliang Qing1, Bo Li, Annette Vu

  • 1Abramson Family Cancer Research Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.

Cancer Cell
|November 17, 2012
PubMed

Insights

Oncogenic Myc drives cancer cell dependence on glutamine (Gln). Gln deprivation triggers apoptosis in Myc-overexpressing cells by inducing PUMA and NOXA via ATF4, offering new therapeutic targets.

Area of Science:

  • Cancer Biology
  • Metabolic Regulation
  • Molecular Oncology

Background:

  • Oncogenic Myc proteins reprogram cellular metabolism, creating a dependency on exogenous glutamine (Gln) for survival.
  • Glutamine deprivation selectively induces apoptosis in Myc-overexpressing cancer cells through incompletely understood mechanisms.

Purpose of the Study:

  • To elucidate the molecular mechanisms by which glutamine deprivation induces apoptosis in Myc-transformed cells, using MYCN-amplified neuroblastoma as a model.
  • To identify potential therapeutic strategies targeting Myc-driven cancers by exploiting their metabolic vulnerabilities.

Main Methods:

  • Utilized MYCN-amplified neuroblastoma cell models.
  • Investigated the roles of apoptosis executors PUMA, NOXA, and TRB3.
  • Analyzed the involvement of the ATF4 transcription factor and p53.
  • Assessed the contribution of glutamate-oxaloacetate transaminase and glutamate dehydrogenase in Gln homeostasis.
  • Evaluated the efficacy of ATF4 agonists and glutaminolysis inhibitors in vitro and in vivo.

Main Results:

  • Identified PUMA, NOXA, and TRB3 as key mediators of apoptosis in Gln-starved Myc-transformed cells.
  • Demonstrated that Gln depletion induces apoptosis via ATF4-dependent, p53-independent upregulation of PUMA and NOXA.
  • Showed that MYC-transformed cells rely on glutamate-oxaloacetate transaminase and glutamate dehydrogenase for Gln metabolism and survival.
  • Confirmed that ATF4 agonists and glutaminolysis inhibitors effectively induce apoptosis and inhibit tumor growth.

Conclusions:

  • Myc sensitizes cancer cells to apoptosis upon glutamine deprivation through specific molecular pathways involving ATF4, PUMA, and NOXA.
  • Targeting ATF4 or glutaminolysis represents a promising therapeutic approach for Myc-driven cancers, including neuroblastoma.

More Related Videos

Intracellular Phosphoflow Cytometry of Acute Myeloid Leukemia Patient-Derived Xenotransplants07:38

Intracellular Phosphoflow Cytometry of Acute Myeloid Leukemia Patient-Derived Xenotransplants

Published on: June 6, 2025

Related Concept Videos

Abnormal Proliferation02:23

Abnormal Proliferation

Under normal conditions, most adult cells remain in a non-proliferative state unless stimulated by internal or external factors to replace lost cells. Abnormal cell proliferation is a condition in which the cell's growth exceeds and is uncoordinated with normal cells. In such situations, cell division persists in the same excessive manner even after cessation of the stimuli, leading to persistent tumors. The tumor arises from the damaged cells that replicate to pass the damage to the daughter...
mTOR Signaling and Cancer Progression03:03

mTOR Signaling and Cancer Progression

The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
The Intrinsic Apoptotic Pathway01:31

The Intrinsic Apoptotic Pathway

Internal cellular stress, such as cellular injury or hypoxia, triggers intrinsic apoptosis. The B-cell lymphoma 2 (Bcl-2) family of proteins are the primary regulators of the intrinsic apoptotic pathway. For example, during DNA damage, checkpoint proteins, such as Ataxia Telangiectasia Mutated (ATM protein) and Checkpoints Factor-2 (Chk2) proteins, are activated. These proteins phosphorylate p53 which further activates pro-apoptotic proteins, such as Bax, Bak, PUMA, and Noxa, and inhibits...
Autophagic Cell Death01:18

Autophagic Cell Death

Christian de Duve discovered “autophagy,” a process in which cellular components are engulfed by membrane-bound organelles called autophagosomes. The autophagosomes then fuse with lysosomes to digest the enclosed contents. Autophagy is generally activated in cells to prevent cell death. However, cell death is triggered when the damage is beyond repair.
Autophagy and Apoptosis
Autophagy can activate apoptosis. In normal conditions, the autophagy activating protein Beclin-1 and pro-apoptotic...