Metallothionein-3 Promotes Cisplatin Chemoresistance Remodelling in Neuroblastoma

Overview

Journal Sci Rep

Specialty Science

Date 2021 Mar 22

PMID 33750814

Citations 12

Authors

Miguel Angel Merlos Rodrigo

Hana Michalkova

Vladislav Strmiska

Berta Casar

Piero Crespo

Vivian de Los Rios

J Ignacio Casal

Yazan Haddad

Roman Guran

Tomas Eckschlager

Petra Pokorna

Zbynek Heger

Vojtech Adam

Affiliations

Soon will be listed here.

Abstract

Metallothionein-3 has poorly characterized functions in neuroblastoma. Cisplatin-based chemotherapy is a major regimen to treat neuroblastoma, but its clinical efficacy is limited by chemoresistance. We investigated the impact of human metallothionein-3 (hMT3) up-regulation in neuroblastoma cells and the mechanisms underlying the cisplatin-resistance. We confirmed the cisplatin-metallothionein complex formation using mass spectrometry. Overexpression of hMT3 decreased the sensitivity of neuroblastoma UKF-NB-4 cells to cisplatin. We report, for the first time, cisplatin-sensitive human UKF-NB-4 cells remodelled into cisplatin-resistant cells via high and constitutive hMT3 expression in an in vivo model using chick chorioallantoic membrane assay. Comparative proteomic analysis demonstrated that several biological pathways related to apoptosis, transport, proteasome, and cellular stress were involved in cisplatin-resistance in hMT3 overexpressing UKF-NB-4 cells. Overall, our data confirmed that up-regulation of hMT3 positively correlated with increased cisplatin-chemoresistance in neuroblastoma, and a high level of hMT3 could be one of the causes of frequent tumour relapses.

Citing Articles

Metallothionein-3 is a multifunctional driver that modulates the development of sorafenib-resistant phenotype in hepatocellular carcinoma cells.

Rodrigo M, Michalkova H, Jimenez A, Petrlak F, Do T, Sivak L Biomark Res. 2024; 12(1):38.

PMID: 38594765 PMC: 11003176. DOI: 10.1186/s40364-024-00584-y.

Technical Implications of the Chicken Embryo Chorioallantoic Membrane Assay to Elucidate Neuroblastoma Biology.

Patino-Morales C, Jaime-Cruz R, Ramirez-Fuentes T, Villavicencio-Guzman L, Salazar-Garcia M Int J Mol Sci. 2023; 24(19).

PMID: 37834193 PMC: 10572838. DOI: 10.3390/ijms241914744.

Cancer chemoresistance and its mechanisms: Associated molecular factors and its regulatory role.

Kannampuzha S, Gopalakrishnan A Med Oncol. 2023; 40(9):264.

PMID: 37550533 DOI: 10.1007/s12032-023-02138-y.

Chick chorioallantoic membrane (CAM) assay for the evaluation of the antitumor and antimetastatic activity of platinum-based drugs in association with the impact on the amino acid metabolism.

Mitrevska K, Rodrigo M, Cernei N, Michalkova H, Splichal Z, Hynek D Mater Today Bio. 2023; 19:100570.

PMID: 36824411 PMC: 9941372. DOI: 10.1016/j.mtbio.2023.100570.

Sevoflurane reverses cisplatin resistance in neuroblastoma cells through the linc00473/miR-490-5p/AKT1 axis.

Li H, Fu X, Guo H, Sun Y, Wang D, Zhang Z Saudi Med J. 2022; 43(11):1209-1216.

PMID: 36379536 PMC: 10043911. DOI: 10.15537/smj.2022.43.11.20220549.

References

Nakamura Y, Suganami A, Fukuda M, Hasan M, Yokochi T, Takatori A . Identification of novel candidate compounds targeting TrkB to induce apoptosis in neuroblastoma. Cancer Med. 2014; 3(1):25-35. PMC: 3930387. DOI: 10.1002/cam4.175. View

Yu W, Chen Y, Dubrulle J, Stossi F, Putluri V, Sreekumar A . Cisplatin generates oxidative stress which is accompanied by rapid shifts in central carbon metabolism. Sci Rep. 2018; 8(1):4306. PMC: 5844883. DOI: 10.1038/s41598-018-22640-y. View

Don S, Verrills N, Liaw T, Liu M, Norris M, Haber M . Neuronal-associated microtubule proteins class III beta-tubulin and MAP2c in neuroblastoma: role in resistance to microtubule-targeted drugs. Mol Cancer Ther. 2004; 3(9):1137-46. View

West A, Hidalgo J, Eddins D, Levin E, Aschner M . Metallothionein in the central nervous system: Roles in protection, regeneration and cognition. Neurotoxicology. 2008; 29(3):489-503. PMC: 2486367. DOI: 10.1016/j.neuro.2007.12.006. View

Rodrigo M, Buchtelova H, Jimenez A, Adam P, Babula P, Heger Z . Transcriptomic Landscape of Cisplatin-Resistant Neuroblastoma Cells. Cells. 2019; 8(3). PMC: 6469049. DOI: 10.3390/cells8030235. View

Kmiecik A, Pula B, Suchanski J, Olbromski M, Gomulkiewicz A, Owczarek T . Metallothionein-3 Increases Triple-Negative Breast Cancer Cell Invasiveness via Induction of Metalloproteinase Expression. PLoS One. 2015; 10(5):e0124865. PMC: 4416915. DOI: 10.1371/journal.pone.0124865. View

Escosura-Muniz A, Espinoza-Castaneda M, Chamorro-Garcia A, Rodriguez-Hernandez C, de Torres C, Merkoci A . In situ monitoring of PTHLH secretion in neuroblastoma cells cultured onto nanoporous membranes. Biosens Bioelectron. 2018; 107:62-68. DOI: 10.1016/j.bios.2018.01.064. View

Yamashita M, Hirohashi Y, Torigoe T, Kusumoto H, Murai A, Imagawa T . Dnajb8, a Member of the Heat Shock Protein 40 Family Has a Role in the Tumor Initiation and Resistance to Docetaxel but Is Dispensable for Stress Response. PLoS One. 2016; 11(1):e0146501. PMC: 4709114. DOI: 10.1371/journal.pone.0146501. View

Weinberg F, Ramnath N, Nagrath D . Reactive Oxygen Species in the Tumor Microenvironment: An Overview. Cancers (Basel). 2019; 11(8). PMC: 6721577. DOI: 10.3390/cancers11081191. View

10.

Fuqua S, Oesterreich S, Hilsenbeck S, Von Hoff D, Eckardt J, Osborne C . Heat shock proteins and drug resistance. Breast Cancer Res Treat. 1994; 32(1):67-71. DOI: 10.1007/BF00666207. View

11.

Chen S, Russell W, Russell D . Combining chemical labeling, bottom-up and top-down ion-mobility mass spectrometry to identify metal-binding sites of partially metalated metallothionein. Anal Chem. 2013; 85(6):3229-37. DOI: 10.1021/ac303522h. View

12.

Huang D, Sherman B, Lempicki R . Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc. 2009; 4(1):44-57. DOI: 10.1038/nprot.2008.211. View

13.

Manor E, Kapelushnik J, Joshua B, Bodner L . Metastatic neuroblastoma of the mandible: a cytogenetic and molecular genetic study. Eur Arch Otorhinolaryngol. 2011; 269(8):1967-71. DOI: 10.1007/s00405-011-1863-9. View

14.

Hishikawa Y, Koji T, Dhar D, Kinugasa S, Yamaguchi M, Nagasue N . Metallothionein expression correlates with metastatic and proliferative potential in squamous cell carcinoma of the oesophagus. Br J Cancer. 1999; 81(4):712-20. PMC: 2362883. DOI: 10.1038/sj.bjc.6690753. View

15.

Lokman N, Elder A, Ricciardelli C, Oehler M . Chick chorioallantoic membrane (CAM) assay as an in vivo model to study the effect of newly identified molecules on ovarian cancer invasion and metastasis. Int J Mol Sci. 2012; 13(8):9959-9970. PMC: 3431839. DOI: 10.3390/ijms13089959. View

16.

Ohtomo N, Tomiya T, Tanoue Y, Inoue Y, Nishikawa T, Ikeda H . Expression of α-taxilin in hepatocellular carcinoma correlates with growth activity and malignant potential of the tumor. Int J Oncol. 2010; 37(6):1417-23. DOI: 10.3892/ijo_00000793. View

17.

Maleckaite R, Zalimas A, Bakavicius A, Jankevicius F, Jarmalaite S, Daniunaite K . DNA methylation of metallothionein genes is associated with the clinical features of renal cell carcinoma. Oncol Rep. 2019; 41(6):3535-3544. DOI: 10.3892/or.2019.7109. View

18.

Kawahara B, Ramadoss S, Chaudhuri G, Janzen C, Sen S, Mascharak P . Carbon monoxide sensitizes cisplatin-resistant ovarian cancer cell lines toward cisplatin via attenuation of levels of glutathione and nuclear metallothionein. J Inorg Biochem. 2018; 191:29-39. DOI: 10.1016/j.jinorgbio.2018.11.003. View

19.

Massague J, Obenauf A . Metastatic colonization by circulating tumour cells. Nature. 2016; 529(7586):298-306. PMC: 5029466. DOI: 10.1038/nature17038. View

20.

Hur G, Cho S, Kim C, Kim M, Bae S, Nam S . Manganese superoxide dismutase expression correlates with chemosensitivity in human gastric cancer cell lines. Clin Cancer Res. 2003; 9(15):5768-75. View