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

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

Abstract


Background and purpose: Breast cancer (BC) is one of the major causes of female cancer-related death.             It has recently been demonstrated that metabolic reprogramming including alteration in lipid metabolism             is indicated in various types of cancer. The enzymes of the acyl-coenzyme A synthetase long-chain family (ACSLs) are responsible for converting fatty acids to their corresponding fatty acyl-coenzyme A esters which are essential for some lipid metabolism pathways. ACSL4 is one of the isoforms of ACSLs and has            a marked preference for arachidonic and eicosapentaenoic acids. The objective of this study was to evaluate ACSL4 expression, its prognostic significance, and its correlation with p53 tumor suppressor in BC patients.

Experimental approach: In this study 55 pairs of fresh samples of BC and adjacent non-cancerous tissue were used to analyze ACSL4 expression, using real-time polymerase chain reaction and immunohistochemistry (IHC) staining. The expression of other studied variables was also examined using the IHC technique.

Findings / Results: ACSL4 expression was significantly higher in BC tissues compared to the adjacent normal tissue. This upregulation was negatively correlated with Ki-67 and age, and positively correlated  with p53 status. The correlation between ACSL4 and p53 may indicate the role of p53 in the regulation of lipid metabolism in cancer cells, in addition to its role in the regulation of ferroptosis cell death.

Conclusion and implications: Our results indicated that the expression of ACSL4 may be considered as               a prognostic indicator and potential therapeutic target in BC. However, further studies are needed to confirm the significance of these findings.


Keywords


ACSL4; Breast cancer; p53; Tumor suppressor.

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Wang D, Yin L, Wei J, Yang Z, Jiang G. ATP citrate lyase is increased in human breast cancer, depletion of which promotes apoptosis. Tumor Biol. 2017;39(4):1-10.

Azordegan N, Fraser V, Le K, Hillyer LM, Ma DW, Fischer G, et al. Carcinogenesis alters fatty acid profile in breast tissue. Mol Cell Biochem. 2013;374(1-2):223-232.

Chen WC, Wang CY, Hung YH, Weng TY, Yen MC, Lai MD. Systematic analysis of gene expression alterations and clinical outcomes for long-chain acyl-coenzyme a synthetase family in cancer. PLoS One. 2016;11(5):1-23.

Wang D, Yin L, Wei J, Yang Z, Jiang G. ATP citrate lyase is increased in human breast cancer, depletion of which promotes apoptosis. Tumour Biol. 2017;39(4). DOI: 10.1177/1010428317698338.

Wu X, Deng F, Li Y, Daniels G, Du X, Ren Q, et al. ACSL4 promotes prostate cancer growth, invasion and hormonal resistance. Oncotarget. 2015;6(42):44849-44863.

Rossi Sebastiano M, Konstantinidou G. Targeting long chain acyl-CoA synthetases for cancer therapy. Int J Mol Sci. 2019;20(15):1-16.

Cooke M, Orlando U, Maloberti P, Podestá EJ, Maciel FC. Tyrosine phosphatase SHP2 regulates the expression of acyl-CoA synthetase ACSL4. J Lipid Res. 2011;52(11):1936-1948.

Xie Y, Zhu S, Song X, Sun X, Fan Y, Liu J, et al. The tumor suppressor p53 limits ferroptosis by blocking DPP4 activity. Cell Rep. 2017;20(7):1692-1704.

Belkaid A, Ouellette RJ, Surette ME. 17β-estradiol-induced ACSL4 protein expression promotes an invasive phenotype in estrogen receptor positive mammary carcinoma cells. Carcinogenesis. 2017;38(4):402-410.

Boroughs LK, DeBerardinis RJ. Metabolic pathways promoting cancer cell survival and growth. Nat Cell Biol. 2015;17(4):351-369.

Gnanapradeepan K, Basu S, Barnoud T, Budina-Kolomets A, Kung CP, Murphy ME. The p53 tumor suppressor in the control of metabolism and ferroptosis. Front Endocrinol (Lausanne). 2018;9:124-130.

Kaller M, Liffers ST, Oeljeklaus S, Kuhlmann K, Röh S, Hoffmann R, et al. Genome-wide characterization of miR-34a induced changes in protein and mRNA expression by a combined pulsed SILAC and microarray analysis. Mol Cell Proteomics. 2011;10(8):1-16.

Reisi P, Eidelkhani N, Rafiee L, Kazemi M, Radahmadi M, Alaei H. Effects of doxepin on gene expressions of Bcl-2 family, TNF-α, MAP kinase 14, and Akt1 in the hippocampus of rats exposed to stress. Res Pharm Sci. 2017;12(1):15-20.

Saadatian‐Elahi M, Norat T, Goudable J, Riboli E. Biomarkers of dietary fatty acid intake and the risk of breast cancer: a meta‐analysis. Int J Cancer. 2004;111(4):584-591.

Wang YP, Lei QY. Perspectives of reprogramming breast cancer metabolism. Adv Exp Med Biol. 2017;1026:217-232.

Ye X, Zhang Y, Wang X, Li Y, Gao Y. Tumor‐suppressive functions of long‐chain acyl‐CoA synthetase 4 in gastric cancer. IUBMB Life. 2016;68(4):320-327.

Yen MC, Kan JY, Hsieh CJ, Kuo PL, Hou MF, Hsu YL. Association of long-chain acyl-coenzyme A synthetase 5 expression in human breast cancer by estrogen receptor status and its clinical significance. Oncol Rep. 2017;37(6):3253-3260.

Iqbal BM, Buch A. Hormone receptor (ER, PR, HER2/neu) status and proliferation index marker (Ki-67) in breast cancers: Their onco-pathological correlation, shortcomings and future trends. Med J DY Patil Univ. 2016;9(6):674-679.

Dunnwald LK, Rossing MA, Li CI. Hormone receptor status, tumor characteristics, and prognosis: a prospective cohort of breast cancer patients. Breast Cancer Res. 2007;9(1):1-10.

Cianfrocca M, Goldstein LJ. Prognostic and predictive factors in early-stage breast cancer. Oncologist. 2004;9(6):606-616.

Monaco ME, Creighton CJ, Lee P, Zou X, Topham MK, Stafforini DM. Expression of long-chain fatty Acyl-CoA synthetase 4 in breast and prostate cancers is associated with sex steroid hormone receptor negativity. Transl Oncol. 2010;3(2):91-98.

Ragab HM, Samy N, Afify M, El Maksoud NA, Shaaban HM. Assessment of Ki-67 as a potential biomarker in patients with breast cancer. J Genet Eng Biotechnol. 2018;16(2):479-84.

Chia SK, Wykoff CC, Watson PH, Han C, Leek RD, Pastorek J, et al. Prognostic significance of a novel hypoxia-regulated marker, carbonic anhydrase IX, in invasive breast carcinoma. J Clin Oncol. 2001;19(16):3660-3668.

Milićević Z, Bajić V, Živković L, Kasapović J, Andjelković U, Spremo-Potparević B. Identification of p53 and its isoforms in human breast carcinoma cells. ScientificWorldJournal. 2014;2014:1-10.

Yang P, Du CW, Kwan M, Liang SX, Zhang GJ. The impact of p53 in predicting clinical outcome of breast cancer patients with visceral metastasis. Sci Rep. 2013;3:1-6.

Dookeran KA, Dignam JJ, Ferrer K, Sekosan M, McCaskill-Stevens W, Gehlert S. p53 as a marker of prognosis in African-American women with breast cancer. Ann Surg Oncol. 2010;17(5):1398-1405.

Jin MS, Park IA, Kim JY, Chung YR, Im SA, Lee KH, et al. New insight on the biological role of p53 protein as a tumor suppressor: re-evaluation of its clinical significance in triple-negative breast cancer. Tumour Biol. 2016;37(8):11017-11024.

Pan Y, Yuan Y, Liu G, Wei Y. P53 and Ki-67 as prognostic markers in triple-negative breast cancer patients. PLoS One. 2017;12(2):1-13.

Parrales A, Iwakuma T. p53 as a regulator of lipid metabolism in cancer. Int J Mol Sci. 2016;17(12): 1-11.

Liu J, Zhang C, Hu W, Feng Z. Tumor suppressor p53 and its mutants in cancer metabolism. Cancer Lett. 2015;356(2 Pt A):197-203.

Bai C, Gao Y, Zhang X, Yang W, Guan W. MicroRNA-34c acts as a bidirectional switch in the maturation of insulin-producing cells derived from mesenchymal stem cells. Oncotarget. 2017;8(63):106844-106857.

Navarro F, Lieberman J. miR-34 and p53: new insights into a complex functional relationship. PLoS One. 2015;10(7):1-23.

Doll S, Proneth B, Tyurina YY, Panzilius E, Kobayashi S, Ingold I, et al. ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition. Nat Chem Biol. 2017;13(1):91-115.

Wu X, Li Y, Wang J, Wen X, Marcus MT, Daniels G, et al. Long chain fatty Acyl-CoA synthetase 4 is a biomarker for and mediator of hormone resistance in human breast cancer. PLoS One. 2013;8(10):1-20.


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