SLC6A8 Knockdown Suppresses the Invasion and Migration of Human Hepatocellular Carcinoma Huh-7 and Hep3B Cells

Yuan, Linhong; Wu, Xian; Li, Wen Chuan; Zhuo, Chenyi; Xu, Zuoming; Tan, Chuan Ping; Ma, Rihai; Wang, JianChu; Pu, Jian

doi:10.1177/1533033820983029

Cited by 9 publications

(9 citation statements)

References 41 publications

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“…The altered level and activity of creatine transporter can be connected with tumour development. Analysis of literature data showed that an elevated level of SLC6A8 was noticed in breast [ 55 ], non-small cell lung [ 50 ] or hepatocellular cancers [ 56 ]. In clinical trials, inhibition of CT-1 is tested for the treatment of colorectal carcinoma [ 57 ].…”

Section: Clinical Significance Of Slc6a6 and Slc6a8 Transportersmentioning

confidence: 99%

Taurine and Creatine Transporters as Potential Drug Targets in Cancer Therapy

Stary

Bajda

2023

IJMS

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Cancer cells are characterized by uncontrolled growth, proliferation, and impaired apoptosis. Tumour progression could be related to poor prognosis and due to this fact, researchers have been working on novel therapeutic strategies and antineoplastic agents. It is known that altered expression and function of solute carrier proteins from the SLC6 family could be associated with severe diseases, including cancers. These proteins were noticed to play important physiological roles through transferring nutrient amino acids, osmolytes, neurotransmitters, and ions, and many of them are necessary for survival of the cells. Herein, we present the potential role of taurine (SLC6A6) and creatine (SLC6A8) transporters in cancer development as well as therapeutic potential of their inhibitors. Experimental data indicate that overexpression of analyzed proteins could be connected with colon or breast cancers, which are the most common types of cancers. The pool of known inhibitors of these transporters is limited; however, one ligand of SLC6A8 protein is currently tested in the first phase of clinical trials. Therefore, we also highlight structural aspects useful for ligand development. In this review, we discuss SLC6A6 and SLC6A8 transporters as potential biological targets for anticancer agents.

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Section: Clinical Significance Of Slc6a6 and Slc6a8 Transportersmentioning

confidence: 99%

Taurine and Creatine Transporters as Potential Drug Targets in Cancer Therapy

Stary

Bajda

2023

IJMS

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“…In tumors, previous study has demonstrated that SLC6A8 is overexpressed in human liver metastases compared with primary colorectal tumors and associated with enhanced colorectal cancer cell survival during hypoxic stress, suggesting the protective effects of SLC6A8 in cancer cells. It was recently reported that SLC6A8 knockdown suppressed the invasion and migration of human hepatocellular carcinoma cells [ 17 ]. Nonetheless, the implications of SLC6A8 in tumor progression remain poorly studied.…”

Section: Introductionmentioning

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

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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.

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“…A recent study demonstrated that creatine promotes cancer metastasis through activation of Smad2/3 ( 20 ). In addition, a study at the cellular level demonstrated that knockdown of SLC6A8 significantly induced apoptosis and inhibited migration and invasion of Hep3B and Huh-7 cells in hepatocellular carcinoma cells ( 21 ). Therefore, there is a promising research potential regarding SLC6A8 , however, fewer relevant reports exist in lung cancer.…”

Section: Introductionmentioning

confidence: 99%

Long Non-Coding RNA AL513318.2 as ceRNA Binding to hsa-miR-26a-5p Upregulates SLC6A8 Expression and Predicts Poor Prognosis in Non-Small Lung Cancer

Fan

Zhou

et al. 2022

Front. Oncol.

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BackgroundStudies have demonstrated that the regulatory role of competitive endogenous RNA (ceRNA) networks is closely related to tumorigenesis, which provides new targets for tumor therapy. In this study, the focus was to explore the ceRNA networks that regulate SLC6A8 expression and their prognosis in non-small cell lung cancer (NSCLC).MethodsFirstly, the Cancer Genome Atlas (TCGA) data combined with immunohistochemical staining was used to compare SLC6A8 expression in NSCLC tissues and normal tissues. Thereafter, samples from the immunohistochemical staining of NSCLC were integrated with clinical follow-up data for prognostic analysis. The Starbase database was employed to search for SLC6A8-targeted miRNAs and lncRNAs, and survival analysis was performed using clinical data from TCGA to obtain SLC6A8 expression and prognosis-related ceRNA networks. Finally, the prognostic and therapeutic prospects of SLC6A8 in NSCLC were further analyzed from methylation sites and the immune microenvironment.ResultsThe study results revealed that SLC6A8 was significantly overexpressed in NSCLC tissues compared to normal tissues, and clinical follow-up data showed that the overexpression group was associated with poor prognosis. In addition, the Starbase data combined with TCGA clinical data analysis demonstrated that the AL513318.2/hsa-miR-26a-5p/SLC6A8 network regulates SLC6A8 overexpression in NSCLC and is associated with poor prognosis. Methylation analysis revealed that 11 methylation sites were closely associated with the prognosis of NSCLC. In addition, the immune prognostic risk model showed that the high-risk group was associated with a poorer prognosis than the low-risk group, despite showing a better immunotherapy outcome.ConclusionIn summary, the AL513318.2/hsa-miR-26a-5p/SLC6A8 network upregulates SLC6A8 expression in NSCLC and is associated with poor prognosis. Therefore it may be a prognostic biomarker of NSCLC and a potential therapeutic target.

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SLC6A8 Knockdown Suppresses the Invasion and Migration of Human Hepatocellular Carcinoma Huh-7 and Hep3B Cells

Cited by 9 publications

References 41 publications

Taurine and Creatine Transporters as Potential Drug Targets in Cancer Therapy

Taurine and Creatine Transporters as Potential Drug Targets in Cancer Therapy

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

Long Non-Coding RNA AL513318.2 as ceRNA Binding to hsa-miR-26a-5p Upregulates SLC6A8 Expression and Predicts Poor Prognosis in Non-Small Lung Cancer

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