Upregulation of Antioxidant Capacity and Nucleotide Precursor Availability Suffices for Oncogenic Transformation

Zhang, Yang; Xu, Yi; Lu, Wenyun; Ghergurovich, Jonathan M.; Guo, Lili; Blair, Ian A.; Rabinowitz, Joshua D.; Yang, Xiaolu

doi:10.1016/j.cmet.2020.10.002

Cited by 48 publications

(45 citation statements)

References 63 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The aberrantly high level of ROS has detrimental consequences on cell viability through extensive damage of DNA, proteins and organelles [ 29 ]. Antioxidant N-acetyl-L-cysteine (NAC) was considered as an important molecule of antioxidant defense for cellular resistance to exogenous stress [ 30 , 31 ].…”

Section: Resultsmentioning

confidence: 99%

SLC6A8-mediated intracellular creatine accumulation enhances hypoxic breast cancer cell survival via ameliorating oxidative stress

Liu

Sun

et al. 2021

J Exp Clin Cancer Res

View full text Add to dashboard Cite

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.

show abstract

Section: Resultsmentioning

confidence: 99%

SLC6A8-mediated intracellular creatine accumulation enhances hypoxic breast cancer cell survival via ameliorating oxidative stress

Liu

Sun

et al. 2021

J Exp Clin Cancer Res

View full text Add to dashboard Cite

show abstract

“…Although previous studies have suggested that G6PD or the PPP enhances tumor growth by protecting cells from ROS ( 38 ) and promoting nucleotide synthesis ( 16 ), there is a lack of in vivo studies demonstrating the importance of the PPP in tumorigenesis. Although G6pd was not required for Kras -driven mouse LUAD with WT Keap1 ( 18 ), in this study, we demonstrate that G6PD genetic loss or pharmacological inhibition selectively suppresses growth of a genetic subset of LUAD with KEAP1 mutations and NRF2 activation.…”

Section: Discussionmentioning

confidence: 99%

“…Multiple enzymes involved in the oxidative PPP (oxPPP) such as glucose-6-phosphate dehydrogenase (G6PD) and 6-phosphogluconate dehydrogenase (PGD), and in the non-oxPPP such as transaldolase and transketolase (TKT) are transcriptionally activated by NRF2 ( 10 ), leading to increased PPP flux ( 10 , 11 ). G6PD, which catalyzes the first and rate-limiting step of the PPP, accounts for most of the cellular NADPH produced in most cultured cancer cells ( 15 ) and can promote tumor initiation ( 16 ). However, despite the potential importance of the PPP in cancer metabolism, this pathway has not been successfully therapeutically targeted in cancer ( 17 , 18 ).…”

Section: Introductionmentioning

confidence: 99%

Activation of the NRF2 antioxidant program sensitizes tumors to G6PD inhibition

Ding

Chen

et al. 2021

Sci. Adv.

Self Cite

View full text Add to dashboard Cite

show abstract

“…Consistent with this idea, the expression level of glucose-6 phosphate dehydrogenase, a key enzyme in the PPP, was increased in the GSCs cultured at pH 6.8. Zhang et al 49 found that G6PD mediated cellular antioxidant defense and upregulation of nucleotide generation led to tumorigenic transformation in mouse and human cells. Many studies have reported that the aberrant activation of G6PD or H6PD is related to tumorigenesis and malignancy in rapidly growing cancer cells [50][51][52][53] .…”

Section: Discussionmentioning

confidence: 99%

Rewiring of purine metabolism in response to acidosis stress in glioma stem cells

Wang

Zang

et al. 2021

Cell Death Dis

View full text Add to dashboard Cite

Glioma stem cells (GSCs) contribute to therapy resistance and poor outcomes for glioma patients. A significant feature of GSCs is their ability to grow in an acidic microenvironment. However, the mechanism underlying the rewiring of their metabolism in low pH remains elusive. Here, using metabolomics and metabolic flux approaches, we cultured GSCs at pH 6.8 and pH 7.4 and found that cells cultured in low pH exhibited increased de novo purine nucleotide biosynthesis activity. The overexpression of glucose-6-phosphate dehydrogenase, encoded by G6PD or H6PD, supports the metabolic dependency of GSCs on nucleotides when cultured under acidic conditions, by enhancing the pentose phosphate pathway (PPP). The high level of reduced glutathione (GSH) under acidic conditions also causes demand for the PPP to provide NADPH. Taken together, upregulation of G6PD/H6PD in the PPP plays an important role in acidic-driven purine metabolic reprogramming and confers a predilection toward glioma progression. Our findings indicate that targeting G6PD/H6PD, which are closely related to glioma patient survival, may serve as a promising therapeutic target for improved glioblastoma therapeutics. An integrated metabolomics and metabolic flux analysis, as well as considering microenvironment and cancer stem cells, provide a precise insight into understanding cancer metabolic reprogramming.

show abstract

Upregulation of Antioxidant Capacity and Nucleotide Precursor Availability Suffices for Oncogenic Transformation

Cited by 48 publications

References 63 publications

SLC6A8-mediated intracellular creatine accumulation enhances hypoxic breast cancer cell survival via ameliorating oxidative stress

SLC6A8-mediated intracellular creatine accumulation enhances hypoxic breast cancer cell survival via ameliorating oxidative stress

Activation of the NRF2 antioxidant program sensitizes tumors to G6PD inhibition

Rewiring of purine metabolism in response to acidosis stress in glioma stem cells

Contact Info

Product

Resources

About