SLC12A5 promotes hepatocellular carcinoma growth and ferroptosis resistance by inducing ER stress and cystine transport changes

Tong, Qing; Qin, Wei; Li, Zhenghao; Li, Chun; Wang, Zicheng; Chu, Yuan; Xu, Xun-Di

doi:10.1002/cam4.5605

Cited by 9 publications

(11 citation statements)

References 52 publications

(109 reference statements)

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“… 40 Additionally, it has been found that SLC12A5 impedes tumorigenesis in HepG2 cells by impeding cell cycle progression via calcium release into the cytosol during ER stress. 20 While conventionally recognized as a membrane protein crucial for K‐Cl transport, recent evidence unveils that SLC12A5 is also expressed in the nucleus, exerting a tumour‐promoting role. 41 Jiang and colleagues conducted a comprehensive investigation into the role of SLC12A5 across 33 human cancers, demonstrating its potential as a tumour promoter associated with worse overall survival and poor disease‐specific survival.…”

Section: Discussionmentioning

confidence: 99%

“…Tong and colleagues reported that SLC12A5 promotes tumour progression by regulating ER stress and increases ferroptosis resistance in HCC by controlling intracellular redox balance. 20 In this study, our investigation focused on the gene expressions of biomarkers related to ER stress pathways induced by borax in HepG2 cells. Additionally, we explored the connection between borax‐induced ER stress and apoptotic mechanisms, as well as its impact on SLC12A5.…”

Section: Discussionmentioning

confidence: 99%

“… 18 , 19 Additionally, elevated levels of SLC12A5 have been associated with a poor prognosis and the promotion of tumorigenesis in HCC. 20 However, investigations into the effects of SLC12A5 on tumour viability are still in their nascent stages.…”

Section: Introductionmentioning

confidence: 99%

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Borax affects cellular viability by inducing ER stress in hepatocellular carcinoma cells by targeting SLC12A5

Hacioglu,

Oral

2024

J Cellular Molecular Medi

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Hepatocellular carcinoma (HCC) presents a persistent challenge to conventional therapeutic approaches. SLC12A5 is implicated in an oncogenic capacity and facilitates the progression of cancer. The objective of this investigation is to scrutinize the inhibitory effects of borax on endoplasmic reticulum (ER)‐stress and apoptosis mediated by SLC12A5 in HepG2 cells. Initially, we evaluated the cytotoxic impact of borax on both HL‐7702 and HepG2 cell lines. Subsequently, the effects of borax on cellular morphology and the cell cycle of these lines were examined. Following this, we explored the impact of borax treatment on the mRNA and protein expression levels of SLC12A5, C/EBP homologous protein (CHOP), glucose‐regulated protein‐78 (GRP78), activating transcription factor‐6 (ATF6), caspase‐3 (CASP3), and cytochrome c (CYC) in these cellular populations. The determined IC50 value of borax for HL‐7702 cells was 40.8 mM, whereas for HepG2 cells, this value was 22.6 mM. The concentrations of IC50 (22.6 mM) and IC75 (45.7 mM) of borax in HepG2 cells did not manifest morphological aberrations in HL‐7702 cells. Conversely, these concentrations in HepG2 cells induced observable morphological and nuclear abnormalities, resulting in cell cycle arrest in the G1/G0 phase. Additionally, the levels of SLC12A5, ATF6, CHOP, GRP78, CASP3, and CYC were elevated in HepG2 cells in comparison to HL‐7702 cells. Moreover, SLC12A5 levels decreased following borax treatment in HepG2 cells, whereas ATF6, CHOP, GRP78, CASP3, and CYC levels exhibited a significant increase. In conclusion, our data highlight the potential therapeutic effects of borax through the regulation of ER stress in HCC by targeting SLC12A5.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Borax affects cellular viability by inducing ER stress in hepatocellular carcinoma cells by targeting SLC12A5

Hacioglu,

Oral

2024

J Cellular Molecular Medi

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“…( 110 ), curcumin promoted iron apoptosis in colorectal cancer by controlling the expression of vital iron apoptosis indicators Fer 1, SLC7A11, GSH, MDA, and ROS through the PI3K/mTOR pathway. Recent studies have shown that the mTOR-related signaling system can either promote or inhibit ferroptosis in hepatocellular carcinoma cells ( 111 , 112 ). For instance, HU et al.…”

Section: Mechanisms Of Ferroptosis Regulationmentioning

confidence: 99%

Iron accumulation and lipid peroxidation: implication of ferroptosis in hepatocellular carcinoma

Li,

Meng,

Wang

et al. 2024

Front. Endocrinol.

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Ferroptosis is a type of controlled cell death caused by lipid peroxidation, which results in the rupture of the cell membrane. ferroptosis has been repeatedly demonstrated over the past ten years to be a significant factor in a number of diseases. The liver is a significant iron storage organ, thus ferroptosis will have great potential in the treatment of liver diseases. Ferroptosis is particularly prevalent in HCC. In the opening section of this article, we give a general summary of the pertinent molecular mechanisms, signaling pathways, and associated characteristics of ferroptosis. The primary regulating mechanisms during ferroptosis are then briefly discussed, and we conclude by summarizing the development of a number of novel therapeutic strategies used to treat HCC in recent years. Ferroptosis is a crucial strategy for the treatment of HCC and offers new perspectives on the treatment of liver cancer.

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“…Ferroptosis is an iron-dependent form of regulated cell death characterized by the accumulation of lipid peroxides. Ferroptosis resistance, the ability of cells or tissues to evade ferroptotic cell death, has been implicated in the development of cell death and various diseases [1][2][3][4], yet its role in lupus still needs to be depicted. Lupus is an autoimmune disease characterized by hypergammaglobulinemia derived from pathogenic B cell behavior [5][6][7].…”

Section: Introductionmentioning

confidence: 99%

Neutrophil-Derived IL-6 Potentially Drives Ferroptosis Resistance in B Cells in Lupus Kidney

Wang

Shen

et al. 2023

Mediators of Inflammation

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Ferroptosis resistance is vital for B cell development, especially in inflammatory diseases, yet the underlying mechanism is still unclear. In this study, based on the scRNA-seq technique and flow cytometry, we discovered a proportion of neutrophils exhibited upregulated expression of the IL-6 and correlated with the expression of IL-6 receptor and SLC7A11 from B cells in lupus kidney. Moreover, we identified that in lupus kidney, neutrophils could provide IL-6 to facilitate ferroptosis resistance in B cells via SLC7A11, and inhibition of SLC7A11 could significantly enhance ferroptosis in B cells and could decrease B cell proliferation. This study helps understand the crosstalk between neutrophils and B cells in the kidney in the development of lupus.

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SLC12A5 promotes hepatocellular carcinoma growth and ferroptosis resistance by inducing ER stress and cystine transport changes

Abstract: This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 9 publications

References 52 publications

Borax affects cellular viability by inducing ER stress in hepatocellular carcinoma cells by targeting SLC12A5

Borax affects cellular viability by inducing ER stress in hepatocellular carcinoma cells by targeting SLC12A5

Iron accumulation and lipid peroxidation: implication of ferroptosis in hepatocellular carcinoma

Neutrophil-Derived IL-6 Potentially Drives Ferroptosis Resistance in B Cells in Lupus Kidney

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