Evaluation of long-chain acyl-coenzyme A synthetase 4 (ACSL4) expression in human breast cancer

Dinarvand, Negar; Khanahmad, Hossein; Hakimian, Sayyed Mohammadreza; Sheikhi, Abdolkarim; Rashidi, Bahman; Pourfarzam, Morteza

doi:10.4103/1735-5362.278714

Cited by 20 publications

(6 citation statements)

References 32 publications

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“…Basal-like breast cancer cell lines are susceptible to ferroptosis due to the expression of acyl-CoA synthetase long-chain family member 4 (ACSL4) which enriches cellular membranes with long polyunsaturated fatty acids (PUFAs) [ 33 ]. Since ACSL4 is expressed higher in breast cancer compared to the adjacent normal tissue [ 34 ], and PUFAs are targets of lipid peroxidation, cancer cells might be more susceptible to lipid peroxidation and ferroptosis, thus GPX4 is more essential in cancer cells. As a third possibility, as the xCT-positive cancer cells are expected to have increased glutathione production and GPX4 expression, the resulting increased antioxidant capacity may be accompanied by a reduced selective requirement for other anti-ferroptotic or prosurvival signaling activities, meaning that when this xCT/GPX4-mediated protection is removed, these cancer cells are vulnerable compared to ‘nonaddicted’ cells.…”

Section: Discussionmentioning

confidence: 99%

xCT-Driven Expression of GPX4 Determines Sensitivity of Breast Cancer Cells to Ferroptosis Inducers

et al. 2021

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Inducers of ferroptosis such as the glutathione depleting agent Erastin and the GPX4 inhibitor Rsl-3 are being actively explored as potential therapeutics in various cancers, but the factors that determine their sensitivity are poorly understood. Here, we show that expression levels of both subunits of the cystine/glutamate antiporter xCT determine the expression of GPX4 in breast cancer, and that upregulation of the xCT/selenocysteine biosynthesis/GPX4 production axis paradoxically renders the cancer cells more sensitive to certain types of ferroptotic stimuli. We find that GPX4 is strongly upregulated in a subset of breast cancer tissues compared to matched normal samples, and that this is tightly correlated with the increased expression of the xCT subunits SLC7A11 and SLC3A2. Erastin depletes levels of the antioxidant selenoproteins GPX4 and GPX1 in breast cancer cells by inhibiting xCT-dependent extracellular reduction which is required for selenium uptake and selenocysteine biosynthesis. Unexpectedly, while breast cancer cells are resistant compared to nontransformed cells against oxidative stress inducing drugs, at the same time they are hypersensitive to lipid peroxidation and ferroptosis induced by Erastin or Rsl-3, indicating that they are ‘addicted’ to the xCT/GPX4 axis. Our findings provide a strategic basis for targeting the anti-ferroptotic machinery of breast cancer cells depending on their xCT status, which can be further explored.

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Section: Discussionmentioning

confidence: 99%

xCT-Driven Expression of GPX4 Determines Sensitivity of Breast Cancer Cells to Ferroptosis Inducers

et al. 2021

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“… [46] also found a negative correlation between expression of ACSL4 and ER. Besides, ACSL4 is overexpressed in breast cancer tissues compared with adjacent normal tissues [47] . In vitro, ACSL4 inhibition significantly suppresses cell proliferation, invasion, and migration in MDA-MB-231 cell line [ 48 , 49 ].…”

Section: Discussionmentioning

confidence: 99%

Predictive and prognostic impact of ferroptosis-related genes ACSL4 and GPX4 on breast cancer treated with neoadjuvant chemotherapy

Sha¹,

Xu²,

Yuan

et al. 2021

eBioMedicine

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Background Recent evidence shows that inducing ferroptosis may improve efficacy of tumor therapy. However, ferroptosis-related genes have been little studied in patients with breast cancer especially in the neoadjuvant setting. ACSL4 and GPX4 have been well established as the positive and negative regulator of ferroptosis, respectively. This study aimed to explore the predictive value of ACSL4 and GPX4 for patients with breast cancer administered neoadjuvant chemotherapy. Methods This study included patients treated with paclitaxel-cisplatin-based neoadjuvant chemotherapy. Immunohistochemistry staining of ACSL4 and GPX4 was carried out on the core needle biopsy specimens. Logistic regression was performed to explore the predictive biomarkers of pathological complete response (pCR). Survival analyses were examined by log-rank test and Cox proportional hazard regression. Findings A total of 199 patients were included for the analyses. Both ACSL4 expression and ACSL4/GPX4 combination status could serve as independent predictive factors for pCR. The interaction for pCR was observed between ACSL4 and clinical tumor stage. Besides, ACSL4 expression, GPX4 expression, and their combination status were independent prognostic factors for disease-free survival. Analyses of the Kaplan-Meier Plotter database suggested that higher ACSL4 expression is related to better overall survival, and higher GPX4 expression is related to better distant metastasis-free survival. Pathway analyses revealed that ACSL4 and GPX4 might function in crucial pathways including apoptosis, autophagy, cell adhesion, lipid metabolism, etc . Interpretation This study revealed the critical value of ACSL4 and GPX4 serving as novel predictive and prognostic biomarkers for patients with breast cancer receiving neoadjuvant chemotherapy. It might be a novel strategy to induce ferroptosis to promote chemosensitivity. Future studies are required to elucidate the potential mechanisms. Funding This work was supported by Shanghai Natural Science Foundation [grant number 19ZR1431100], Clinical Research Plan of Shanghai Hospital Development Center [grant numbers SHDC2020CR3003A, 16CR3065B, and 12016231], Shanghai “Rising Stars of Medical Talent” Youth Development Program for Youth Medical Talents - Specialist Program [grant number 2018-15], Shanghai “Rising Stars of Medical Talent” Youth Development Program for Outstanding Youth Medical Talents [grant number 2018-16], Shanghai Collaborative Innovation Center for Translational Medicine [grant number TM201908], Multidisciplinary Cross Research Foundation of Shanghai Jiao Tong University [grant numbers YG2017QN49, ZH2018QNA42, and YG2019QNA28], Nurturing Fund of Renji Hospital [grant numbers PYMDT-002, PY2018-IIC-01, PY2018-III-15, and PYIII20-09], Science and Technology Commission of Shanghai Municipality [grant numbers 20DZ2201600 and 15JC1402700], and Shangha...

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“…This correlation appears to be similar to that observed in the treatment of refractory mesenchymal carcinoma cells and clear cell renal carcinoma cells [ 7 ]. ACSL4 is elevated in BC tissues compared with in healthy tissues adjacent to the cancer, and ACSL4 expression is negatively correlated with ER [ 81 , 82 ]. Clinically, radiotherapy upregulates the expression of ACSL4, resulting in increased lipid synthesis and, consequently, oxidative injury, leading to ferroptosis [ 83 ].…”

Section: Association Between Ferroptosis and Bcmentioning

confidence: 99%

“…Clinically, radiotherapy upregulates the expression of ACSL4, resulting in increased lipid synthesis and, consequently, oxidative injury, leading to ferroptosis [ 83 ]. High expression of ACSL4 promotes BC aggressiveness, is a potential prognostic indicator and therapeutic target [ 82 ], and plays a substantial role in radiation resistance in BC by modulating the expression of transporter proteins implicated in cancer resistance via the mTOR pathway and regulating forkhead box protein M1 (FOXM1) [ 84 ].…”

Section: Association Between Ferroptosis and Bcmentioning

confidence: 99%

Role of ferroptosis and ferroptosis-related long non'coding RNA in breast cancer

Xiang,

Yan,

Ren

et al. 2024

Cell Mol Biol Lett

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Ferroptosis, a therapeutic strategy for tumours, is a regulated cell death characterised by the increased accumulation of iron-dependent lipid peroxides (LPO). Tumour-associated long non-coding RNAs (lncRNAs), when combined with traditional anti-cancer medicines or radiotherapy, can improve efficacy and decrease mortality in cancer. Investigating the role of ferroptosis-related lncRNAs may help strategise new therapeutic options for breast cancer (BC). Herein, we briefly discuss the genes and pathways of ferroptosis involved in iron and reactive oxygen species (ROS) metabolism, including the XC−/GSH/GPX4 system, ACSL4/LPCAT3/15-LOX and FSP1/CoQ10/NAD(P)H pathways, and investigate the correlation between ferroptosis and LncRNA in BC to determine possible biomarkers related to ferroptosis.

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Evaluation of long-chain acyl-coenzyme A synthetase 4 (ACSL4) expression in human breast cancer

Cited by 20 publications

References 32 publications

xCT-Driven Expression of GPX4 Determines Sensitivity of Breast Cancer Cells to Ferroptosis Inducers

xCT-Driven Expression of GPX4 Determines Sensitivity of Breast Cancer Cells to Ferroptosis Inducers

Predictive and prognostic impact of ferroptosis-related genes ACSL4 and GPX4 on breast cancer treated with neoadjuvant chemotherapy

Role of ferroptosis and ferroptosis-related long non'coding RNA in breast cancer

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