ACSL3 is an Unfavorable Prognostic Marker in Cholangiocarcinoma Patients and Confers Ferroptosis Resistance in Cholangiocarcinoma Cells

Overview

Journal NPJ Precis Oncol

Publisher Springer Nature

Specialty Oncology

Date 2024 Dec 20

PMID 39706856

Authors

Apiwit Sae-Fung

Nawaporn Vinayavekhin

Bengt Fadeel

Siriporn Jitkaew

Affiliations

Soon will be listed here.

Abstract

Cholangiocarcinoma (CCA) is a bile duct malignancy. Our previous comprehensive analysis showed that ferroptosis-related genes can stratify CCA patients into low-risk and high-risk groups based on survival time. Here, we explored the role of ferroptosis in CCA by analyzing mRNA expression in CCA patients from public databases. We identified acyl-CoA synthetase long chain family member 3 (ACSL3) as a potential ferroptosis suppressor in high-risk CCA patients. Using a panel of CCA cell lines, we confirmed ACSL3 upregulation in CCA cell lines associated with high-risk CCA, correlating this with resistance to the ferroptosis inducer RSL3. Lipidomic analysis revealed increased monounsaturated fatty acid (MUFA)-containing phospholipids in resistant cell lines. ACSL3 silencing sensitized these cells to RSL3. Resistance to ferroptosis was also dependent on exogenous MUFAs and was enhanced by lipid droplet biogenesis inhibition. These findings highlight ACSL3 as a promising target for therapeutic strategies aimed at overcoming ferroptosis resistance in CCA.

References

Leveille C, Mikhaeil J, Turner K, Silvera S, Wilkinson J, Fajardo V . Mitochondrial cristae density: a dynamic entity that is critical for energy production and metabolic power in skeletal muscle. J Physiol. 2017; 595(9):2779-2780. PMC: 5407988. DOI: 10.1113/JP274158. View

Sicklick J, Kato S, Okamura R, Schwaederle M, Hahn M, Williams C . Molecular profiling of cancer patients enables personalized combination therapy: the I-PREDICT study. Nat Med. 2019; 25(5):744-750. PMC: 6553618. DOI: 10.1038/s41591-019-0407-5. View

Kassan A, Herms A, Fernandez-Vidal A, Bosch M, Schieber N, Reddy B . Acyl-CoA synthetase 3 promotes lipid droplet biogenesis in ER microdomains. J Cell Biol. 2013; 203(6):985-1001. PMC: 3871434. DOI: 10.1083/jcb.201305142. View

von Krusenstiern A, Robson R, Qian N, Qiu B, Hu F, Reznik E . Identification of essential sites of lipid peroxidation in ferroptosis. Nat Chem Biol. 2023; 19(6):719-730. PMC: 10238648. DOI: 10.1038/s41589-022-01249-3. View

Chaisaingmongkol J, Budhu A, Dang H, Rabibhadana S, Pupacdi B, Kwon S . Common Molecular Subtypes Among Asian Hepatocellular Carcinoma and Cholangiocarcinoma. Cancer Cell. 2017; 32(1):57-70.e3. PMC: 5524207. DOI: 10.1016/j.ccell.2017.05.009. View

Toshida K, Itoh S, Iseda N, Izumi T, Yoshiya S, Toshima T . Impact of TP53-induced glycolysis and apoptosis regulator on malignant activity and resistance to ferroptosis in intrahepatic cholangiocarcinoma. Cancer Sci. 2023; 115(1):170-183. PMC: 10823267. DOI: 10.1111/cas.15981. View

Ndiaye H, Liu J, Hall A, Minogue S, Morgan M, Waugh M . Immunohistochemical staining reveals differential expression of ACSL3 and ACSL4 in hepatocellular carcinoma and hepatic gastrointestinal metastases. Biosci Rep. 2020; 40(4). PMC: 7198044. DOI: 10.1042/BSR20200219. View

Jusakul A, Cutcutache I, Yong C, Lim J, Huang M, Padmanabhan N . Whole-Genome and Epigenomic Landscapes of Etiologically Distinct Subtypes of Cholangiocarcinoma. Cancer Discov. 2017; 7(10):1116-1135. PMC: 5628134. DOI: 10.1158/2159-8290.CD-17-0368. View

Lee H, Horbath A, Kondiparthi L, Meena J, Lei G, Dasgupta S . Cell cycle arrest induces lipid droplet formation and confers ferroptosis resistance. Nat Commun. 2024; 15(1):79. PMC: 10761718. DOI: 10.1038/s41467-023-44412-7. View

10.

Badgley M, Kremer D, Maurer H, DelGiorno K, Lee H, Purohit V . Cysteine depletion induces pancreatic tumor ferroptosis in mice. Science. 2020; 368(6486):85-89. PMC: 7681911. DOI: 10.1126/science.aaw9872. View

11.

Miyake S, Murai S, Kakuta S, Uchiyama Y, Nakano H . Identification of the hallmarks of necroptosis and ferroptosis by transmission electron microscopy. Biochem Biophys Res Commun. 2020; 527(3):839-844. DOI: 10.1016/j.bbrc.2020.04.127. View

12.

Sae-Fung A, Mutirangura A, Jitkaew S . Identification and validation of a novel ferroptosis-related gene signature for prognosis and potential therapeutic target prediction in cholangiocarcinoma. Front Immunol. 2023; 13:1051273. PMC: 9887182. DOI: 10.3389/fimmu.2022.1051273. View

13.

Liu Y, Lu S, Wu L, Yang L, Yang L, Wang J . The diversified role of mitochondria in ferroptosis in cancer. Cell Death Dis. 2023; 14(8):519. PMC: 10425449. DOI: 10.1038/s41419-023-06045-y. View

14.

Mbah N, Lyssiotis C . Metabolic regulation of ferroptosis in the tumor microenvironment. J Biol Chem. 2022; 298(3):101617. PMC: 8892088. DOI: 10.1016/j.jbc.2022.101617. View

15.

Zou Y, Palte M, Deik A, Li H, Eaton J, Wang W . A GPX4-dependent cancer cell state underlies the clear-cell morphology and confers sensitivity to ferroptosis. Nat Commun. 2019; 10(1):1617. PMC: 6453886. DOI: 10.1038/s41467-019-09277-9. View

16.

Dai E, Chen X, Linkermann A, Jiang X, Kang R, Kagan V . A guideline on the molecular ecosystem regulating ferroptosis. Nat Cell Biol. 2024; 26(9):1447-1457. PMC: 11650678. DOI: 10.1038/s41556-024-01360-8. View

17.

Doll S, Proneth B, Tyurina Y, Panzilius E, Kobayashi S, Ingold I . ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition. Nat Chem Biol. 2016; 13(1):91-98. PMC: 5610546. DOI: 10.1038/nchembio.2239. View

18.

Klasson T, LaGory E, Zhao H, Huynh S, Papandreou I, Moon E . ACSL3 regulates lipid droplet biogenesis and ferroptosis sensitivity in clear cell renal cell carcinoma. Cancer Metab. 2022; 10(1):14. PMC: 9528056. DOI: 10.1186/s40170-022-00290-z. View

19.

Zhang X, Li X, Xia R, Zhang H . Ferroptosis resistance in cancer: recent advances and future perspectives. Biochem Pharmacol. 2023; 219:115933. DOI: 10.1016/j.bcp.2023.115933. View

20.

Banales J, Marin J, Lamarca A, Rodrigues P, Khan S, Roberts L . Cholangiocarcinoma 2020: the next horizon in mechanisms and management. Nat Rev Gastroenterol Hepatol. 2020; 17(9):557-588. PMC: 7447603. DOI: 10.1038/s41575-020-0310-z. View