Hypoxia Suppresses Cysteine Deprivation-induced Cell Death Via ATF4 Regulation in MDA-MB-231 Breast Cancer Cells

Cancer cells are frequently exposed to microenvironmental stresses, including amino acid deprivation and hypoxia, which are often targeted for cancer therapy. Here, we examined the effect of hypoxia in cysteine-deprived breast cancer cells and the mechanism to counteract the hypoxia effect. Cell dea...

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Bibliographic Details
Published in:Anticancer research 2020-03, Vol.40 (3), p.1387-1394
Main Authors: Hong, Sung-Eun, Kim, Mi-Ri, Jang, Se-Kyeong, Seong, Min-Ki, Kim, Hyun-Ah, Noh, Woo Chul, Jin, Hyeon-Ok, Park, In-Chul
Format: Article
Language:English
Subjects:
Activating transcription factor 4
Activating Transcription Factor 4 - metabolism
Amino acids
Annexin V
Apoptosis
Breast cancer
Breast Neoplasms - drug therapy
Breast Neoplasms - metabolism
Breast Neoplasms - pathology
Cancer
Cancer therapies
Cell death
Cell Death - physiology
Cell Hypoxia - physiology
Cell Line, Tumor
Cysteine
Cysteine - antagonists & inhibitors
Cysteine - deficiency
Cysteine - metabolism
Deprivation
Female
Glutamic acid transporter
Humans
Hypoxia
Iodides
Mortality
Polymerase chain reaction
Propidium iodide
Reverse transcription
Sulfasalazine
Sulfasalazine - pharmacology
Therapy
TRAIL protein
Transfection
Up-Regulation
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Summary:Cancer cells are frequently exposed to microenvironmental stresses, including amino acid deprivation and hypoxia, which are often targeted for cancer therapy. Here, we examined the effect of hypoxia in cysteine-deprived breast cancer cells and the mechanism to counteract the hypoxia effect. Cell death was determined by annexin V-FITC and propidium iodide staining. Expression of mRNAs and proteins was determined by reverse transcription polymerase chain reaction and western blot analysis, respectively. Cysteine deprivation or sulfasalazine, a potent inhibitor of cysteine/glutamate transporter, induced cell death by activating transcription factor 4 (ATF4) up-regulation. Hypoxia significantly suppressed cell death and ATF4 up-regulation induced by cysteine deprived conditions. In addition, tumor necrosis factor-related apoptosis-inducing ligand reversed the effect of hypoxia on cysteine deprived conditions. Prevention of hypoxia may be a means for augmenting the effect of amino acid deprivation as a strategy for cancer therapy.
ISSN:0250-7005
1791-7530
DOI:10.21873/anticanres.14080