Mitochondria generate energy and building blocks required for cellular growth and function. The notion that mitochondria are not involved in the cancer growth has been challenged in recent years together with the emerging idea of mitochondria as a promising therapeutic target for oncologic diseases. Pentamethinium salts, cyan dyes with positively charged nitrogen on the benzothiazole or indole part of the molecule, were originally designed as mitochondrial probes. In this study, we show that pentamethinium salts have a strong effect on mitochondria, suppressing cancer cell proliferation and migration. This is likely linked to the strong inhibitory effect of the salts on dihydroorotate dehydrogenase (DHODH)-dependent respiration that has a key role in the de novo pyrimidine synthesis pathway. We also show that pentamethinium salts cause oxidative stress, redistribution of mitochondria, and a decrease in mitochondria mass. In conclusion, pentamethinium salts present novel anti-cancer agents worthy of further studies.
Melanoma phenotype plasticity underlies tumour dissemination and resistance to therapy, yet its regulation is incompletely understood. In vivo switching between a more differentiated, proliferative phenotype and a dedifferentiated, invasive phenotype is directed by the tumour microenvironment. We found that treatment of partially dedifferentiated, invasive A375M2 cells with two structurally unrelated p38 MAPK inhibitors, SB2021920 and BIRB796, induces a phenotype switch in 3D collagen, as documented by increased expression of melanocyte differentiation markers and a loss of invasive phenotype markers. The phenotype is accompanied by morphological change corresponding to amoeboid-mesenchymal transition. We performed RNA sequencing with an Illumina HiSeq platform to fully characterise transcriptome changes underlying the switch. Gene expression results obtained with RNA-seq were validated by comparing them with RT-qPCR. Transcriptomic data generated in the study will extend the present understanding of phenotype plasticity in melanoma and its contribution to invasion and metastasis.
- MeSH
- buněčná diferenciace účinky léků genetika MeSH
- fenotyp MeSH
- genová ontologie MeSH
- imidazoly farmakologie MeSH
- inhibitory proteinkinas farmakologie MeSH
- kolagen metabolismus MeSH
- lidé MeSH
- melanom genetika patologie MeSH
- mitogenem aktivované proteinkinasy p38 antagonisté a inhibitory metabolismus MeSH
- nádorové buněčné linie MeSH
- nádorové mikroprostředí účinky léků genetika MeSH
- naftaleny farmakologie MeSH
- polymerázová řetězová reakce s reverzní transkripcí MeSH
- proliferace buněk účinky léků genetika MeSH
- pyrazoly farmakologie MeSH
- pyridiny farmakologie MeSH
- regulace genové exprese u nádorů účinky léků MeSH
- sekvenování transkriptomu metody MeSH
- stanovení celkové genové exprese metody MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
