| Autor: |
Rodrigo, Miguel Angel Merlos, Michalkova, Hana, Jimenez, Ana Maria Jimenez, Petrlak, Frantisek, Do, Tomas, Sivak, Ladislav, Haddad, Yazan, Kubickova, Petra, de los Rios, Vivian, Casal, J. Ignacio, Serrano-Macia, Marina, Delgado, Teresa C., Boix, Loreto, Bruix, Jordi, Martinez Chantar, Maria L., Adam, Vojtech, Heger, Zbynek |
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| Zdroj: |
Biomarker Research; 4/9/2024, Vol. 12 Issue 1, p1-18, 18p |
| Abstrakt: |
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. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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