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

• Published in: Biomarker research 2024-04, Vol.12 (1), p.38-38, Article 38
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Angiogenesis; Apoptosis; Cell culture; Cell cycle; Cell death; Cell growth; Cellular stress response; Chemotherapy; Chorioallantoic membrane; Cysteine; Development and progression; DNA microarrays; Exocytosis; Experiments; Genetic aspects; Genotype & phenotype; Glycolysis; Health aspects; Hepatitis; Hepatocellular carcinoma; Hepatoma; Homeostasis; Liver cancer; Medical prognosis; Metallothionein; Metallothionein-3; Molecular modelling; Phenotypes; Polymerase chain reaction; Proteomics; Resistance; Scientific equipment and supplies industry; Sorafenib; Spheroids; Survival analysis
• ISSN: 2050-7771; 2050-7771
• DOI: 10.1186/s40364-024-00584-y

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. 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. 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. 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.