Journal article
Hypoxia-Mediated ATF4 Induction Promotes Survival in Detached Conditions in Metastatic Murine Mammary Cancer Cells
Frontiers in oncology, Vol.12, pp.767479-767479
06/30/2022
DOI: 10.3389/fonc.2022.767479
PMCID: PMC9280133
PMID: 35847893
Abstract
Regions of hypoxia are common in solid tumors and drive changes in gene expression that increase risk of cancer metastasis. Tumor cells must respond to the stress of hypoxia by activating genes to modify cell metabolism and antioxidant response to improve survival. The goal of the current study was to determine the effect of hypoxia on cell metabolism and markers of oxidative stress in metastatic (metM-Wnt
lung
) compared with nonmetastatic (M-Wnt) murine mammary cancer cell lines. We show that hypoxia induced a greater suppression of glutamine to glutamate conversion in metastatic cells (13% in metastatic cells compared to 7% in nonmetastatic cells). We also show that hypoxia increased expression of genes involved in antioxidant response in metastatic compared to nonmetastatic cells, including glutamate cysteine ligase catalytic and modifier subunits and malic enzyme 1. Interestingly, hypoxia increased the mRNA level of the transaminase glutamic pyruvic transaminase 2 (Gpt2, 7.7-fold) only in metM-Wnt
lung
cells. The change in Gpt2 expression was accompanied by transcriptional (4.2-fold) and translational (6.5-fold) induction of the integrated stress response effector protein activating transcription factor 4 (ATF4). Genetic depletion ATF4 demonstrated importance of this molecule for survival of hypoxic metastatic cells in detached conditions. These findings indicate that more aggressive, metastatic cancer cells utilize hypoxia for metabolic reprogramming and induction of antioxidant defense, including activation of ATF4, for survival in detached conditions.
Details
- Title: Subtitle
- Hypoxia-Mediated ATF4 Induction Promotes Survival in Detached Conditions in Metastatic Murine Mammary Cancer Cells
- Creators
- Violet A. Kiesel - Purdue University West LafayetteMadeline P. Sheeley - Purdue University West LafayetteEmily M. Hicks - Purdue University West LafayetteChaylen Andolino - Purdue University West LafayetteShawn S. Donkin - Purdue University West LafayetteMichael K. Wendt - Purdue University West LafayetteStephen D. Hursting - University of North Carolina at Chapel HillDorothy Teegarden - Purdue University West Lafayette
- Resource Type
- Journal article
- Publication Details
- Frontiers in oncology, Vol.12, pp.767479-767479
- DOI
- 10.3389/fonc.2022.767479
- PMID
- 35847893
- PMCID
- PMC9280133
- NLM abbreviation
- Front Oncol
- ISSN
- 2234-943X
- eISSN
- 2234-943X
- Publisher
- Frontiers Media S.A
- Grant note
- ;
- Language
- English
- Date published
- 06/30/2022
- Academic Unit
- Internal Medicine
- Record Identifier
- 9984460331302771
Metrics
5 Record Views