Metallothionein-3 is a multifunctional driver that modulates the development of sorafenib-resistant phenotype in hepatocellular carcinoma cells
Abstract Background & aims Metallothionein-3 (hMT3) is a structurally unique member of the metallothioneins family of low-mass cysteine-rich proteins. hMT3 has poorly characterized functions, and its importance for hepatocellular carcinoma (HCC) cells has not yet been elucidated. Therefore, we i...
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| Format: | Article |
| Language: | English |
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BMC
2024-04-01
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| Series: | Biomarker Research |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s40364-024-00584-y |
| _version_ | 1797209213684940800 |
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| author | Miguel Angel Merlos Rodrigo Hana Michalkova Ana Maria Jimenez Jimenez Frantisek Petrlak Tomas Do Ladislav Sivak Yazan Haddad Petra Kubickova Vivian de los Rios J. Ignacio Casal Marina Serrano-Macia Teresa C. Delgado Loreto Boix Jordi Bruix Maria L. Martinez Chantar Vojtech Adam Zbynek Heger |
| author_facet | Miguel Angel Merlos Rodrigo Hana Michalkova Ana Maria Jimenez Jimenez Frantisek Petrlak Tomas Do Ladislav Sivak Yazan Haddad Petra Kubickova Vivian de los Rios J. Ignacio Casal Marina Serrano-Macia Teresa C. Delgado Loreto Boix Jordi Bruix Maria L. Martinez Chantar Vojtech Adam Zbynek Heger |
| author_sort | Miguel Angel Merlos Rodrigo |
| collection | DOAJ |
| description | Abstract Background & aims Metallothionein-3 (hMT3) is a structurally unique member of the metallothioneins family of low-mass cysteine-rich proteins. hMT3 has poorly characterized functions, and its importance for hepatocellular carcinoma (HCC) cells has not yet been elucidated. Therefore, we investigated the molecular mechanisms driven by hMT3 with a special emphasis on susceptibility to sorafenib. Methods Intrinsically sorafenib-resistant (BCLC-3) and sensitive (Huh7) cells with or without up-regulated hMT3 were examined using cDNA microarray and methods aimed at mitochondrial flux, oxidative status, cell death, and cell cycle. In addition, in ovo/ex ovo chick chorioallantoic membrane (CAM) assays were conducted to determine a role of hMT3 in resistance to sorafenib and associated cancer hallmarks, such as angiogenesis and metastastic spread. Molecular aspects of hMT3-mediated induction of sorafenib-resistant phenotype were delineated using mass-spectrometry-based proteomics. Results The phenotype of sensitive HCC cells can be remodeled into sorafenib-resistant one via up-regulation of hMT3. hMT3 has a profound effect on mitochondrial respiration, glycolysis, and redox homeostasis. Proteomic analyses revealed a number of hMT3-affected biological pathways, including exocytosis, glycolysis, apoptosis, angiogenesis, and cellular stress, which drive resistance to sorafenib. Conclusions hMT3 acts as a multifunctional driver capable of inducing sorafenib-resistant phenotype of HCC cells. Our data suggest that hMT3 and related pathways could serve as possible druggable targets to improve therapeutic outcomes in patients with sorafenib-resistant HCC. |
| first_indexed | 2024-04-24T09:51:08Z |
| format | Article |
| id | doaj.art-7a0c75ad3012498a9f15fd7e736949c9 |
| institution | Directory Open Access Journal |
| issn | 2050-7771 |
| language | English |
| last_indexed | 2024-04-24T09:51:08Z |
| publishDate | 2024-04-01 |
| publisher | BMC |
| record_format | Article |
| series | Biomarker Research |
| spelling | doaj.art-7a0c75ad3012498a9f15fd7e736949c92024-04-14T11:23:33ZengBMCBiomarker Research2050-77712024-04-0112111810.1186/s40364-024-00584-yMetallothionein-3 is a multifunctional driver that modulates the development of sorafenib-resistant phenotype in hepatocellular carcinoma cellsMiguel Angel Merlos Rodrigo0Hana Michalkova1Ana Maria Jimenez Jimenez2Frantisek Petrlak3Tomas Do4Ladislav Sivak5Yazan Haddad6Petra Kubickova7Vivian de los Rios8J. Ignacio Casal9Marina Serrano-Macia10Teresa C. Delgado11Loreto Boix12Jordi Bruix13Maria L. Martinez Chantar14Vojtech Adam15Zbynek Heger16Department of Chemistry and Biochemistry, Mendel University in BrnoDepartment of Chemistry and Biochemistry, Mendel University in BrnoDepartment of Chemistry and Biochemistry, Mendel University in BrnoDepartment of Chemistry and Biochemistry, Mendel University in BrnoDepartment of Chemistry and Biochemistry, Mendel University in BrnoDepartment of Chemistry and Biochemistry, Mendel University in BrnoDepartment of Chemistry and Biochemistry, Mendel University in BrnoDepartment of Chemistry and Biochemistry, Mendel University in BrnoDepartment of Cellular and Molecular Medicine and Proteomic Facility, Centro de Investigaciones Biológicas (CIB-CSIC)Department of Cellular and Molecular Medicine and Proteomic Facility, Centro de Investigaciones Biológicas (CIB-CSIC)Liver Disease Laboratory, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA)Liver Disease Laboratory, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA)Barcelona-Clínic Liver Cancer Group, Liver Unit, Institut d’Investigacions Biomèdiques August Pi I SunyerBarcelona-Clínic Liver Cancer Group, Liver Unit, Institut d’Investigacions Biomèdiques August Pi I SunyerLiver Disease Laboratory, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA)Department of Chemistry and Biochemistry, Mendel University in BrnoDepartment of Chemistry and Biochemistry, Mendel University in BrnoAbstract Background & aims Metallothionein-3 (hMT3) is a structurally unique member of the metallothioneins family of low-mass cysteine-rich proteins. hMT3 has poorly characterized functions, and its importance for hepatocellular carcinoma (HCC) cells has not yet been elucidated. Therefore, we investigated the molecular mechanisms driven by hMT3 with a special emphasis on susceptibility to sorafenib. Methods Intrinsically sorafenib-resistant (BCLC-3) and sensitive (Huh7) cells with or without up-regulated hMT3 were examined using cDNA microarray and methods aimed at mitochondrial flux, oxidative status, cell death, and cell cycle. In addition, in ovo/ex ovo chick chorioallantoic membrane (CAM) assays were conducted to determine a role of hMT3 in resistance to sorafenib and associated cancer hallmarks, such as angiogenesis and metastastic spread. Molecular aspects of hMT3-mediated induction of sorafenib-resistant phenotype were delineated using mass-spectrometry-based proteomics. Results The phenotype of sensitive HCC cells can be remodeled into sorafenib-resistant one via up-regulation of hMT3. hMT3 has a profound effect on mitochondrial respiration, glycolysis, and redox homeostasis. Proteomic analyses revealed a number of hMT3-affected biological pathways, including exocytosis, glycolysis, apoptosis, angiogenesis, and cellular stress, which drive resistance to sorafenib. Conclusions hMT3 acts as a multifunctional driver capable of inducing sorafenib-resistant phenotype of HCC cells. Our data suggest that hMT3 and related pathways could serve as possible druggable targets to improve therapeutic outcomes in patients with sorafenib-resistant HCC.https://doi.org/10.1186/s40364-024-00584-yMetallothionein-3ResistanceHepatocellular carcinomaSorafenib |
| spellingShingle | Miguel Angel Merlos Rodrigo Hana Michalkova Ana Maria Jimenez Jimenez Frantisek Petrlak Tomas Do Ladislav Sivak Yazan Haddad Petra Kubickova Vivian de los Rios J. Ignacio Casal Marina Serrano-Macia Teresa C. Delgado Loreto Boix Jordi Bruix Maria L. Martinez Chantar Vojtech Adam Zbynek Heger Metallothionein-3 is a multifunctional driver that modulates the development of sorafenib-resistant phenotype in hepatocellular carcinoma cells Biomarker Research Metallothionein-3 Resistance Hepatocellular carcinoma Sorafenib |
| title | Metallothionein-3 is a multifunctional driver that modulates the development of sorafenib-resistant phenotype in hepatocellular carcinoma cells |
| title_full | Metallothionein-3 is a multifunctional driver that modulates the development of sorafenib-resistant phenotype in hepatocellular carcinoma cells |
| title_fullStr | Metallothionein-3 is a multifunctional driver that modulates the development of sorafenib-resistant phenotype in hepatocellular carcinoma cells |
| title_full_unstemmed | Metallothionein-3 is a multifunctional driver that modulates the development of sorafenib-resistant phenotype in hepatocellular carcinoma cells |
| title_short | Metallothionein-3 is a multifunctional driver that modulates the development of sorafenib-resistant phenotype in hepatocellular carcinoma cells |
| title_sort | metallothionein 3 is a multifunctional driver that modulates the development of sorafenib resistant phenotype in hepatocellular carcinoma cells |
| topic | Metallothionein-3 Resistance Hepatocellular carcinoma Sorafenib |
| url | https://doi.org/10.1186/s40364-024-00584-y |
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