Login Register Cart 0
Generic placeholder image

Current Pharmaceutical Design

Editor-in-Chief

ISSN (Print): 1381-6128
ISSN (Online): 1873-4286

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Silencing MFHAS1 Induces Pyroptosis via the JNK-activated NF-κB/Caspase1/ GSDMD Signal Axis in Breast Cancer

Author(s): Yue Jin, Mingrui Zhai, Rongyi Cao, Hongmin Yu, Chunli Wu and Yanhong Liu*

Volume 29, Issue 42, 2023

Published on: 02 November, 2023

Page: [3408 - 3420] Pages: 13

DOI: 10.2174/0113816128268130231026054649

Price: $65

Abstract

Introduction: Breast cancer has emerged as the most widespread cancer globally surpassing lung cancer, and has become a primary cause of mortality among women. While MFHAS1 has been implicated in the pathophysiology of various diseases, its precise involvement in breast cancer remains unclear.

Methods: This study endeavors to elucidate the regulatory function of MFHAS1 in breast cancer cell pyroptosis and the associated molecular mechanisms. Our findings indicate that the inhibition of MFHAS1 can impede the proliferation and invasion of breast cancer cells, while also inducing cell pyroptosis via caspase1-dependent activation of GSDMD.

Results: This process results in the cleavage of cell membranes, leading to the release of inflammatory factors and LDH. Subsequent investigations revealed that the silencing of MFHAS1 can promote JNK phosphorylation, thereby activating the JNK signaling cascade. Notably, this effect can be counteracted by the JNK-specific inhibitor sp600125. Ultimately, our investigation substantiated the identical function of MFHAS1 in breast cancer tissue derived from animal models.

Conclusion: To summarize, our findings demonstrate that the inhibition of MFHAS1 elicits pyroptosis in human breast cancer cells through the facilitation of JNK phosphorylation and the activation of the downstream NF-κB/caspase-1/GSDMD signaling cascade, thereby proposing the prospect of MFHAS1 as a viable therapeutic target for breast cancer.

Keywords: Breast cancer, pyroptosis, MFHAS1, JNK, caspase-1, lung cancer.

« Previous
[1]
Larkin L. Breast cancer genetics and risk assessment: An overview for the clinician. Climacteric 2023; 26(3): 229-34.
[http://dx.doi.org/10.1080/13697137.2023.2184254] [PMID: 37011658]
[2]
Wilkinson L, Gathani T. Understanding breast cancer as a global health concern. Br J Radiol 2022; 95(1130): 20211033.
[http://dx.doi.org/10.1259/bjr.20211033] [PMID: 34905391]
[3]
Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2022. CA Cancer J Clin 2022; 72(1): 7-33.
[http://dx.doi.org/10.3322/caac.21708] [PMID: 35020204]
[4]
Kashyap D, Pal D, Sharma R, et al. Global increase in breast cancer incidence: Risk factors and preventive measures. BioMed Res Int 2022; 2022: 1-16.
[http://dx.doi.org/10.1155/2022/9605439] [PMID: 35480139]
[5]
Fahad Ullah M. Breast cancer: Current perspectives on the disease status. Adv Exp Med Biol 2019; 1152: 51-64.
[http://dx.doi.org/10.1007/978-3-030-20301-6_4] [PMID: 31456179]
[6]
Trapani D, Ginsburg O, Fadelu T, et al. Global challenges and policy solutions in breast cancer control. Cancer Treat Rev 2022; 104: 102339.
[http://dx.doi.org/10.1016/j.ctrv.2022.102339] [PMID: 35074727]
[7]
Yu P, Zhang X, Liu N, Tang L, Peng C, Chen X. Pyroptosis: Mechanisms and diseases. Signal Transduct Target Ther 2021; 6(1): 128.
[http://dx.doi.org/10.1038/s41392-021-00507-5] [PMID: 33776057]
[8]
Yang F, Bettadapura SN, Smeltzer MS, Zhu H, Wang S. Pyroptosis and pyroptosis-inducing cancer drugs. Acta Pharmacol Sin 2022; 43(10): 2462-73.
[http://dx.doi.org/10.1038/s41401-022-00887-6] [PMID: 35288674]
[9]
Du T, Gao J, Li P, et al. Pyroptosis, metabolism, and tumor immune microenvironment. Clin Transl Med 2021; 11(8): e492.
[http://dx.doi.org/10.1002/ctm2.492] [PMID: 34459122]
[10]
Fang Y, Tian S, Pan Y, et al. Pyroptosis: A new frontier in cancer. Biomed Pharmacother 2020; 121: 109595.
[http://dx.doi.org/10.1016/j.biopha.2019.109595] [PMID: 31710896]
[11]
Loveless R, Bloomquist R, Teng Y. Pyroptosis at the forefront of anticancer immunity. J Exp Clin Cancer Res 2021; 40(1): 264.
[http://dx.doi.org/10.1186/s13046-021-02065-8] [PMID: 34429144]
[12]
Rao Z, Zhu Y, Yang P, et al. Pyroptosis in inflammatory diseases and cancer. Theranostics 2022; 12(9): 4310-29.
[http://dx.doi.org/10.7150/thno.71086] [PMID: 35673561]
[13]
Li L, Jiang M, Qi L, et al. Pyroptosis, a new bridge to tumor immunity. Cancer Sci 2021; 112(10): 3979-94.
[http://dx.doi.org/10.1111/cas.15059] [PMID: 34252266]
[14]
Yan H, Luo B, Wu X, et al. Cisplatin induces pyroptosis via activation of MEG3/NLRP3/caspase-1/GSDMD pathway in triple-negative breast cancer. Int J Biol Sci 2021; 17(10): 2606-21.
[http://dx.doi.org/10.7150/ijbs.60292] [PMID: 34326697]
[15]
Wang H, Sun P, Chen W, et al. High glucose stimulates expression of MFHAS1 to mitigate inflammation via Akt/HO-1 pathway in human umbilical vein endothelial cells. Inflammation 2018; 41(2): 400-8.
[http://dx.doi.org/10.1007/s10753-017-0696-0] [PMID: 29168081]
[16]
Shi Q, Xiong B, Zhong J, Wang H, Ma D, Miao C. MFHAS1 suppresses TLR4 signaling pathway via induction of PP2A C subunit cytoplasm translocation and inhibition of c-Jun dephosphorylation at Thr239. Mol Immunol 2017; 88: 79-88.
[http://dx.doi.org/10.1016/j.molimm.2017.06.017] [PMID: 28609714]
[17]
Zhong J, Wang H, Chen W, et al. Ubiquitylation of MFHAS1 by the ubiquitin ligase praja2 promotes M1 macrophage polarization by activating JNK and p38 pathways. Cell Death Dis 2017; 8(5): e2763.
[http://dx.doi.org/10.1038/cddis.2017.102] [PMID: 28471450]
[18]
Liu X, Zhang Z, Ruan J, et al. Inflammasome-activated gasdermin D causes pyroptosis by forming membrane pores. Nature 2016; 535(7610): 153-8.
[http://dx.doi.org/10.1038/nature18629] [PMID: 27383986]
[19]
Alonso Guervós M, Álvarez Marcos C, LLorente JL, Sampedro Nuño A, Suárez C, Hermsen M. Genetic differences between primary larynx and pharynx carcinomas and their matched lymph node metastases by multiplex ligation-dependent probe amplification. Oral Oncol 2009; 45(7): 600-4.
[http://dx.doi.org/10.1016/j.oraloncology.2008.08.005] [PMID: 18952489]
[20]
Dihanich S. MASL1: A neglected ROCO protein. Biochem Soc Trans 2012; 40(5): 1090-4.
[http://dx.doi.org/10.1042/BST20120127] [PMID: 22988871]
[21]
Chen W, Xu Y, Zhong J, et al. MFHAS1 promotes colorectal cancer progress by regulating polarization of tumor-associated macrophages via STAT6 signaling pathway. Oncotarget 2016; 7(48): 78726-35.
[http://dx.doi.org/10.18632/oncotarget.12807] [PMID: 27783989]
[22]
Ibrahim J, Op de Beeck K, Fransen E, et al. Methylation analysis of Gasdermin E shows great promise as a biomarker for colorectal cancer. Cancer Med 2019; 8(5): 2133-45.
[http://dx.doi.org/10.1002/cam4.2103] [PMID: 30993897]
[23]
Gao J, Qiu X, Xi G, et al. Downregulation of GSDMD attenuates tumor proliferation via the intrinsic mitochondrial apoptotic pathway and inhibition of EGFR/Akt signaling and predicts a good prognosis in non-small cell lung cancer. Oncol Rep 2018; 40(4): 1971-84.
[http://dx.doi.org/10.3892/or.2018.6634] [PMID: 30106450]
[24]
Hou J, Zhao R, Xia W, et al. PD-L1-mediated gasdermin C expression switches apoptosis to pyroptosis in cancer cells and facilitates tumour necrosis. Nat Cell Biol 2020; 22(10): 1264-75.
[http://dx.doi.org/10.1038/s41556-020-0575-z] [PMID: 32929201]
[25]
Tan Y, Sun R, Liu L, et al. Tumor suppressor DRD2 facilitates M1 macrophages and restricts NF-κB signaling to trigger pyroptosis in breast cancer. Theranostics 2021; 11(11): 5214-31.
[http://dx.doi.org/10.7150/thno.58322] [PMID: 33859743]
[26]
Kovacs SB, Miao EA. Gasdermins: Effectors of pyroptosis. Trends Cell Biol 2017; 27(9): 673-84.
[http://dx.doi.org/10.1016/j.tcb.2017.05.005] [PMID: 28619472]
[27]
Huang Y, Xu W, Zhou R. NLRP3 inflammasome activation and cell death. Cell Mol Immunol 2021; 18(9): 2114-27.
[http://dx.doi.org/10.1038/s41423-021-00740-6] [PMID: 34321623]
[28]
Wei X, Xie F, Zhou X, et al. Role of pyroptosis in inflammation and cancer. Cell Mol Immunol 2022; 19(9): 971-92.
[http://dx.doi.org/10.1038/s41423-022-00905-x] [PMID: 35970871]

Rights & Permissions Print Cite
Article Metrics
30
2
Wayfinder Image
© 2024 Bentham Science Publishers | Privacy Policy