Maslinic Acid Induces Autophagy and Ferroptosis Via Transcriptomic and Metabolomic Reprogramming in Prostate Cancer Cells

Overview

Journal Front Pharmacol

Date 2024 Dec 3

PMID 39624845

Authors

Fen Hu

Yuxi Sun

Yunfeng Zhang

Jiaxin Chen

Yingzi Deng

Yifei Li

Ruobing Li

Juan Zhang

Yongping Liang

Yan Liu

Shuqing Wang

Mi Li

Lina Zhao

Yuwei Liu

Xiaodong Gong

Haifeng Cai

Shouqin Gu

Affiliations

Soon will be listed here.

Abstract

Prostate cancer has the second highest incidence among male malignancies. Only a few studies exist on the inhibitory effects of maslinic acid (MA) on prostate cancer. Herein we found that MA inhibits prostate cancer cell proliferation by decreasing CDK2, CDK4, and CDK6 expression and concurrently increasing p27, Rb, p-Rb expression. Further, MA was observed to induce prostate cancer cell autophagy by increasing the expression of p53, p-p53, ULK1, Beclin1, Atg7, and Atg5 and the ratio of LC3-II/I and concurrently decreasing the expression of ERK1/2 and mTOR. In addition, MA induced RM-1 cell ferroptosis by regulating glutathione, glutamate, and oxidized glutathione concentrations, inhibiting activity, and downregulating GPX4 expression. Integrated metabolome and transcriptome analysis led to the identification of key pathways (e.g., pathways in cancer and glutathione metabolism). Real-time quantitative PCR confirmed that MA regulates the expression of , , and . , we demonstrated that 50 mg/kg MA significantly inhibited the growth of tumors established using RM-1 cells. To summarize, we report that MA inhibits prostate cancer cell growth both and by inducing autophagy and ferroptosis via transcriptomic and metabolomic reprogramming.

References

Wang D, Tang S, Zhang Q . Maslinic acid suppresses the growth of human gastric cells by inducing apoptosis via inhibition of the interleukin-6 mediated Janus kinase/signal transducer and activator of transcription 3 signaling pathway. Oncol Lett. 2017; 13(6):4875-4881. PMC: 5453006. DOI: 10.3892/ol.2017.6073. View

Yu L, Xie X, Cao X, Chen J, Chen G, Chen Y . The Anticancer Potential of Maslinic Acid and Its Derivatives: A Review. Drug Des Devel Ther. 2021; 15:3863-3879. PMC: 8437384. DOI: 10.2147/DDDT.S326328. View

Dorff T, Blanchard M, Adkins L, Luebbert L, Leggett N, Shishido S . PSCA-CAR T cell therapy in metastatic castration-resistant prostate cancer: a phase 1 trial. Nat Med. 2024; 30(6):1636-1644. PMC: 11186768. DOI: 10.1038/s41591-024-02979-8. View

Yap W, Khoo K, Lim S, Yeo C, Lim Y . Proteomic analysis of the molecular response of Raji cells to maslinic acid treatment. Phytomedicine. 2011; 19(2):183-91. DOI: 10.1016/j.phymed.2011.08.058. View

Li Q, Li Z, Liu C, Xu M, Li T, Wang Y . Maslinic Acid Ameliorates Myocardial Ischemia Reperfusion Injury-Induced Oxidative Stress via Activating Nrf2 and Inhibiting NF-[Formula: see text]B Pathways. Am J Chin Med. 2023; 51(4):929-951. DOI: 10.1142/S0192415X2350043X. View

Lee S, Hwang N, Seok B, Lee S, Lee S, Chung S . Autophagy mediates an amplification loop during ferroptosis. Cell Death Dis. 2023; 14(7):464. PMC: 10368698. DOI: 10.1038/s41419-023-05978-8. View

Kang R, Kroemer G, Tang D . The tumor suppressor protein p53 and the ferroptosis network. Free Radic Biol Med. 2018; 133:162-168. PMC: 6251771. DOI: 10.1016/j.freeradbiomed.2018.05.074. View

Ooi K, Poo C, Subramaniam M, Cordell G, Lim Y . Maslinic acid exerts anticancer effects by targeting cancer hallmarks. Phytomedicine. 2023; 110:154631. DOI: 10.1016/j.phymed.2022.154631. View

Park S, Nho C, Kwon D, Kang Y, Lee K, Yoon Park J . Maslinic acid inhibits the metastatic capacity of DU145 human prostate cancer cells: possible mediation via hypoxia-inducible factor-1α signalling. Br J Nutr. 2012; 109(2):210-22. DOI: 10.1017/S0007114512000967. View

10.

Hu X, He Y, Han Z, Liu W, Liu D, Zhang X . PNO1 inhibits autophagy-mediated ferroptosis by GSH metabolic reprogramming in hepatocellular carcinoma. Cell Death Dis. 2022; 13(11):1010. PMC: 9709074. DOI: 10.1038/s41419-022-05448-7. View

11.

Livak K, Schmittgen T . Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 2002; 25(4):402-8. DOI: 10.1006/meth.2001.1262. View

12.

Lu K, Yang M, Peng S, Chen J, Chen P, Chen H . Maslinic Acid Induces DNA Damage and Impairs DNA Repair in Human Cervical Cancer HeLa Cells. Anticancer Res. 2020; 40(12):6869-6877. DOI: 10.21873/anticanres.14709. View

13.

Li C, Yang Z, Zhai C, Qiu W, Li D, Yi Z . Maslinic acid potentiates the anti-tumor activity of tumor necrosis factor alpha by inhibiting NF-kappaB signaling pathway. Mol Cancer. 2010; 9:73. PMC: 2907730. DOI: 10.1186/1476-4598-9-73. View

14.

Wang K, Zhu X, Yin Y . Maslinic Acid Enhances Docetaxel Response in Human Docetaxel-Resistant Triple Negative Breast Carcinoma MDA-MB-231 Cells Regulating MELK-FoxM1-ABCB1 Signaling Cascade. Front Pharmacol. 2020; 11:835. PMC: 7295941. DOI: 10.3389/fphar.2020.00835. View

15.

Tian L, Ji H, Wang W, Han X, Zhang X, Li X . Mitochondria-targeted pentacyclic triterpenoid carbon dots for selective cancer cell destruction via inducing autophagy, apoptosis, as well as ferroptosis. Bioorg Chem. 2022; 130:106259. DOI: 10.1016/j.bioorg.2022.106259. View

16.

Fu X, Liu Z, Li R, Yin J, Sun H, Zhu C . Amelioration of hydrolyzed guar gum on high-fat diet-induced obesity: Integrated hepatic transcriptome and metabolome. Carbohydr Polym. 2022; 297:120051. DOI: 10.1016/j.carbpol.2022.120051. View

17.

Sahebkar A, Foroutan Z, Katsiki N, Jamialahmadi T, Mantzoros C . Ferroptosis, a new pathogenetic mechanism in cardiometabolic diseases and cancer: Is there a role for statin therapy?. Metabolism. 2023; 146:155659. DOI: 10.1016/j.metabol.2023.155659. View

18.

Li Q, Chen K, Zhang T, Jiang D, Chen L, Jiang J . Understanding sorafenib-induced ferroptosis and resistance mechanisms: Implications for cancer therapy. Eur J Pharmacol. 2023; 955:175913. DOI: 10.1016/j.ejphar.2023.175913. View

19.

Zhang S, Ding D, Zhang X, Shan L, Liu Z . Maslinic acid induced apoptosis in bladder cancer cells through activating p38 MAPK signaling pathway. Mol Cell Biochem. 2014; 392(1-2):281-7. DOI: 10.1007/s11010-014-2038-y. View

20.

Jeong S, Kim J, Park E, Baek M, Bae J . Inhibitory functions of maslinic acid on particulate matter-induced lung injury through TLR4-mTOR-autophagy pathways. Environ Res. 2020; 183:109230. DOI: 10.1016/j.envres.2020.109230. View