SLC6A8-mediated intracellular creatine accumulation enhances hypoxic breast cancer cell survival via ameliorating oxidative stress
Li Q, Liu M, Sun Y, Jin T, Zhu P, Wan X, Hou Y, Tu G
Journal of experimental & clinical cancer research : CR · 32 citations
How it was studied
- Design
- In vitro/mechanistic study (classified by our AI screen)
- Studied in
- People, plus animal or lab work
- Main outcome
- Clinical events such as disease or death
Who paid for it
- Funding
- Independent funding
- Government
- Innovative Research Group Project of the National Natural Science Foundation of China
- Government
- National Natural Science Foundation of China
- University or hospital
- Chongqing Medical University
- Grants
- National Natural Science Foundation of China (NSFC81874199); Innovative Research Group Project of the National Natural Science Foundation of China (NSFC 81472476); National Natural Science Foundation of China (81472476); National Natural Science Foundation of China (31671481); National Natural Science Foundation of China (81874199); Innovative Research Group Project of the National Natural Science Foundation of China (NSFC 31671481); Innovative Research Group Project of the National Natural Science Foundation of China (NSFC 81874199); National Natural Science Foundation of China (NSFC81472476); National Natural Science Foundation of China (81372398); Innovative Research Group Project of the National Natural Science Foundation of China (NSFC 81372398)
Based on 3 listed funder(s) and full-text disclosure statement.
Publication
- Published
- 2021-05-14 · J Exp Clin Cancer Res · vol. 40 · issue 1 · p. 168
- Publisher
- BioMed Central
- Cited
- 44 citations · more than 96% of similar papers · 4.5× the field average
- Impact
- Top 10% most cited in its field
- References
- 56 works
- Access
- Open access (journal) · CC-BY
- Research areas
- Muscle metabolism and nutrition · Cancer, Hypoxia, and Metabolism · Cancer, Lipids, and Metabolism
- Keywords
- Oxidative stress, Intracellular, Breast cancer, Apoptosis, Creatine, Hypoxia (environmental), Cancer research, Medicine, Chemistry, Cancer, Endocrinology, Internal medicine, Biology, Cell biology, Biochemistry, Oxygen
- MeSH
- cell line, tumor, animals, humans, mice, mice, nude, creatine, nerve tissue proteins, cell proliferation, cell hypoxia, oxidative stress, middle aged, female, plasma membrane neurotransmitter transport proteins, mcf-7 cells, heterografts, triple negative breast neoplasms
8 authors
From CN
- Qiao LiChildren's Hospital of Chongqing Medical University; Chongqing Medical University
- Manran LiuChildren's Hospital of Chongqing Medical University; Chongqing Medical University
- Yan SunChongqing Medical University
- Ting JinChildren's Hospital of Chongqing Medical University; Chongqing Medical University
- Peng‐Peng ZhuChildren's Hospital of Chongqing Medical University; Chongqing Medical University
- Xueying WanChildren's Hospital of Chongqing Medical University; Chongqing Medical University
Abstract
Background
Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, with poor prognosis and limited treatment options. Hypoxia is a key hallmark of TNBC. Metabolic adaptation promotes progression of TNBC cells that are located within the hypoxic tumor regions. However, it is not well understood regarding the precise molecular mechanisms underlying the regulation of metabolic adaptions by hypoxia.
Methods
RNA sequencing was performed to analyze the gene expression profiles in MDA-MB-231 cell line (20% O2 and 1% O2). Expressions of Slc6a8, which encodes the creatine transporter protein, were detected in breast cancer cells and tissues by quantitative real-time PCR. Immunohistochemistry was performed to detect SLC6A8 protein abundances in tumor tissues. Clinicopathologic correlation and overall survival were evaluated by chi-square test and Kaplan-Meier analysis, respectively. Cell viability assay and flow cytometry analysis with Annexin V/PI double staining were performed to investigate the impact of SLC6A8-mediated uptake of creatine on viability of hypoxic TNBC cells. TNBC orthotopic mouse model was used to evaluate the effects of creatine in vivo.
Results
SLC6A8 was aberrantly upregulated in TNBC cells in hypoxia. SLC6A8 was drastically overexpressed in TNBC tissues and its level was tightly associated with advanced TNM stage, higher histological grade and worse overall survival of TNBC patients. We found that SLC6A8 was transcriptionally upregulated by p65/NF-κB and mediated accumulation of intracellular creatine in hypoxia. SLC6A8-mediated accumulation of creatine promoted survival and suppressed apoptosis via maintaining redox homeostasis in hypoxic TNBC cells. Furthermore, creatine was required to facilitate tumor growth in xenograft mouse models. Mechanistically, intracellular creatine bolstered cell antioxidant defense by reducing mitochondrial activity and oxygen consumption rates to reduce accumulation of intracellular reactive oxygen species, ultimately activating AKT-ERK signaling, the activation of which protected the viability of hypoxic TNBC cells via mediating the upregulation of Ki-67 and Bcl-2, and the downregulation of Bax and cleaved Caspase-3.
Conclusions
Our study indicates that SLC6A8-mediated creatine accumulation plays an important role in promoting TNBC progression, and may provide a potential therapeutic strategy option for treatment of SLC6A8 high expressed TNBC.
Abstract via Europe PMC. Copyright remains with the authors or publisher (CC BY).
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