New inhibitor targeting Acyl-CoA synthetase 4 reduces breast and prostate tumor growth, therapeutic resistance and steroidogenesis

Castillo, Ana Fernanda; Orlando, Ulises Daniel; Maloberti, Paula; Prada, Jesica Giselle; Dattilo, Melina Andrea; Solano, Ángela R.; Bigi, Maria de Las Mercedes; Medrano, Mayra Agustina Ríos; Torres, María T.; Indo, Sebastián; Caroca, Graciela; Contreras, Héctor R.; Marelli, Belkis Ester; Salinas, Facundo; Salvetti, Natalia Raquel; Ortega, Hugo Héctor; Menna, Pablo Lorenzano; Szajnman, Sergio H.; Gómez, Daniel E.; Rodríguez, Juan B.; Podestá, Ernesto J.

doi:10.1007/s00018-020-03679-5

Cited by 44 publications

(41 citation statements)

References 66 publications

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“…While we did not detect any impact on c-Myc protein levels (data not shown), other ACSL4-dependent processes cannot be excluded. For example, ACSL4 contributes to de novo steroid synthesis, and chemical inhibition of ACSL4 was reported to reduce tumor growth in steroid-dependent models of breast and prostate cancer [ 48 ]. Consequently, future investigations should aim to dissect the relative contribution of ferroptosis-dependent and ferroptosis-independent roles of ACSL4 in promoting liver carcinogenesis.…”

Section: Discussionmentioning

confidence: 99%

ACSL4-dependent ferroptosis does not represent a tumor-suppressive mechanism but ACSL4 rather promotes liver cancer progression

et al. 2022

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Ferroptosis is a novel type of programmed cell death that differs from apoptosis in that it involves iron-dependent peroxidation of membrane phospholipids. Its role in a variety of human disorders, including cancer has been hypothesized in recent years. While it may function as an endogenous tumor suppressor in a variety of cancers, its role during initiation and progression of liver cancer, particularly hepatocellular carcinoma (HCC), is yet unknown. Because HCC is most commonly found in chronically injured livers, we utilized two well-established mouse models of chronic injury-dependent HCC formation: Treatment with streptozotocin and high-fat diet as metabolic injury model, as well as treatment with diethylnitrosamine and carbon tetrachloride as toxic injury model. We used mice with hepatocyte-specific deletion of Acsl4, a key mediator of ferroptosis, to explore the significance of ferroptotic cell death in hepatocytes, the cell type of origin for HCC. Surprisingly, preventing ferroptotic cell death in hepatocytes by deleting Acsl4 does not increase the formation of HCC. Furthermore, Acsl4-deficient livers display less fibrosis and proliferation, especially in the HCC model of toxic damage. Intriguingly, in this model, the absence of ACSL4-dependent processes such as ferroptosis significantly slow down the growth of HCC. These findings suggest that during HCC formation in a chronically injured liver, ferroptotic cell death is not an endogenous tumor-suppressive mechanism. Instead, we find that ACSL4-dependent processes have an unanticipated cancer-promoting effect during HCC formation, which is most likely due to aggravated liver damage as demonstrated by increased hepatic fibrosis. Previous studies suggested that ferroptosis might have beneficial effects for patients during HCC therapy. As a result, during HCC progression and therapy, ferroptosis may have both cancer-promoting and cancer-inhibitory effects, respectively.

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Section: Discussionmentioning

confidence: 99%

ACSL4-dependent ferroptosis does not represent a tumor-suppressive mechanism but ACSL4 rather promotes liver cancer progression

et al. 2022

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“…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 ]. Taking the evidence together, aggressive biological behavior is indicated to ACSL4 overexpressed tumors.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, ACSL4 might sensitize breast cancer cells to cytotoxic drugs through promoting BCL11B and inhibiting GDF15, which requires future study to elucidate. Of note, two basic studies found ACSL4 inhibitor PRGL493 slows down breast cancer cell proliferation treated by low-dose chemotherapeutic agents, but the role of ACSL4 in chemotherapy-induced ferroptosis is to be investigated [ 48 , 52 ]. In future, ferroptosis-inducing agents may become a new therapeutic strategy in breast cancer.…”

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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“…ACSL4 expression was 0.386 times higher on average in p53-positive patients than in p53-negative individuals. Additionally, in both breast tumor cells and animal models, the use of PRGL493, a chemical inhibitor of ACSL4 impeding de novo steroid synthesis, could block cell proliferation and tumor growth, and promote the sensitivity of tumor cells to chemotherapeutic and hormonal treatment ( Castillo et al, 2021 ). It is well-known that estrogen receptor (ER) negative breast cancer is less sensitive to chemotherapy, more likely to relapse, leading to poor prognosis.…”

Section: Acyl-coa Synthetase Long-chain Family 4 and Cancermentioning

confidence: 99%

“…Researchers found lncRNAs NEAT1 could promote docetaxel-resistant prostate cancer cells proliferation and invasion by sponging miR-204-5p and miR-34a-5p, leading to an increasing expression of ACSL4 ( Jiang et al, 2020 ). And inhibitor targeting to ACSL4 could reduce prostate cancer growth, therapeutic resistance and steroidogenesis ( Castillo et al, 2021 ).…”

Section: Acyl-coa Synthetase Long-chain Family 4 and Cancermentioning

confidence: 99%

ACSL4 as a Potential Target and Biomarker for Anticancer: From Molecular Mechanisms to Clinical Therapeutics

Hou

Jiang²,

Wen³

et al. 2022

Front. Pharmacol.

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Cancer is a major public health problem around the world and the key leading cause of death in the world. It is well-known that glucolipid metabolism, immunoreaction, and growth/death pattern of cancer cells are markedly different from normal cells. Recently, acyl-CoA synthetase long-chain family 4 (ACSL4) is found be participated in the activation of long chain fatty acids metabolism, immune signaling transduction, and ferroptosis, which can be a promising potential target and biomarker for anticancer. Specifically, ACSL4 inhibits the progress of lung cancer, estrogen receptor (ER) positive breast cancer, cervical cancer and the up-regulation of ACSL4 can improve the sensitivity of cancer cells to ferroptosis by enhancing the accumulation of lipid peroxidation products and lethal reactive oxygen species (ROS). However, it is undeniable that the high expression of ACSL4 in ER negative breast cancer, hepatocellular carcinoma, colorectal cancer, and prostate cancer can also be related with tumor cell proliferation, migration, and invasion. In the present review, we provide an update on understanding the controversial roles of ACSL4 in different cancer cells.

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New inhibitor targeting Acyl-CoA synthetase 4 reduces breast and prostate tumor growth, therapeutic resistance and steroidogenesis

Cited by 44 publications

References 66 publications

ACSL4-dependent ferroptosis does not represent a tumor-suppressive mechanism but ACSL4 rather promotes liver cancer progression

ACSL4-dependent ferroptosis does not represent a tumor-suppressive mechanism but ACSL4 rather promotes liver cancer progression

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

ACSL4 as a Potential Target and Biomarker for Anticancer: From Molecular Mechanisms to Clinical Therapeutics

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