Inspiratory hyperoxia suppresses lung cancer metastasis through a MYC/SLC1A5-dependent metabolic pathway

Abstract

The lack of knowledge about the effect of inspiratory hyperoxia on the lung-specific tumour microenvironment and progression of lung cancer has attracted considerable attention. This study proposes that inspiratory hyperoxia has special significance for the malignant phenotype of lung cancer cells. The effects of different oxygenation parameters on the proliferation, apoptosis, invasion and migration of lung cancer cells were systematically evaluatedin vitroandin vivo. Our results reveal that inspiratory hyperoxia treatment (60% oxygen, 6 h·day−1) not only has no tumour progression-promoting effects, but also suppresses lung cancer metastasis and promotes long-term survival. In addition, we combined transcriptome, proteome and metabolome analysis and found that hyperoxia treatment induced significant intracellular metabolic changes in lung cancer cells. Overall, we established that MYC/SLC1A5-induced metabolic reprogramming and glutamine addiction is a new mechanism that drives lung cancer metastasis, which can be significantly suppressed by inspiratory hyperoxia treatment. These findings are relevant to the debate on the perils, promises and antitumour effect of inspiratory hyperoxia, especially for patients with lung cancer.

Hypoxia signaling in cancer: Implications for therapeutic interventions

“…296 Liu demonstrated that intracellular metabolic reprogramming driven by the MYC/SLC1A5 axis is the main mechanism by which hyperoxia (60% O 2 , 6 h/day) inhibits lung cancer metastasis. 297 The antitumor effect of atmospheric hyperoxia may be due to oxidative stress and increased apoptosis (BCL2-associated X [Bax]/Bcl-2 mRNA expression rate), which is associated with the mitogen-activated protein kinase (MAPK) pathway. 298,299 In the early stage, the antitumor effect of hyperoxia therapy was mainly studied in lung tumors.…”

“…Exposure to hyperoxia before or after drug administration usually promotes tumor development, and further exposure to hyperoxia for a period of time begins to suppress tumor development, but the specific mechanism has not been deeply explored 296 . Liu demonstrated that intracellular metabolic reprogramming driven by the MYC/SLC1A5 axis is the main mechanism by which hyperoxia (60% O 2 , 6 h/day) inhibits lung cancer metastasis 297 . The antitumor effect of atmospheric hyperoxia may be due to oxidative stress and increased apoptosis (BCL2‐associated X [Bax]/Bcl‐2 mRNA expression rate), which is associated with the mitogen‐activated protein kinase (MAPK) pathway 298,299 .…”

HOMER3 promotes non-small cell lung cancer growth and metastasis primarily through GABPB1-mediated mitochondrial metabolism

“…Subsequently, the microarray was incubated with horseradish peroxidase (HRP) polymer-conjugated secondary antibody and stained with 3, 3-diaminobenzidine solution and hematoxylin. The staining intensity score was rated as previously reported [ 18 ]. Briefly, the immunohistochemical staining intensity scores of HOMER3 were evaluated by combining the percentage of immunostained cells with the staining intensity.…”

“…The extracellular acidification rate (ECAR) and oxygen consumption rate (OCR) were measured using an Agilent Seahorse XFe96 extracellular flux analyzer (Agilent Technologies Inc.) as previously described [ 18 ].…”

Amino acid transporters within the solute carrier superfamily: Underappreciated proteins and novel opportunities for cancer therapy

“…During hyperoxia (60% oxygen), MYC expression is decreased which leads to the downregulation of its downstream target gene, SLC1A5 . Then, the disturbance in glutamine uptake and catabolism, and inhibition of invasion and metastasis is happened [ 54 ]. Also, the results of a study by Alfarsi et al.…”