Deep insights into the response of human cervical carcinoma cells to a new cyano enone-bearing triterpenoid soloxolone methyl: a transcriptome analysis
| Autor: | Nariman F. Salakhutdinov, Evgeniya B. Logashenko, Marina A. Zenkova, Andrey V. Markov, Alexander E. Kel, Oksana V. Salomatina |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Cell type SERCA Endoplasmic reticulum Geldanamycin Cell biology soloxolone methyl Transcriptome CDDO-Me 03 medical and health sciences chemistry.chemical_compound 030104 developmental biology 0302 clinical medicine Oncology chemistry Regulatory sequence cytoscape 030220 oncology & carcinogenesis Unfolded protein response cervical carcinoma Transcription factor Research Paper mechanism of action |
| Zdroj: | Oncotarget |
| ISSN: | 1949-2553 |
| Popis: | Semisynthetic triterpenoids, bearing cyano enone functionality in ring A, are considered now as novel promising anti-tumor agents. However, despite the large-scale studies, their effects on cervical carcinoma cells and, moreover, mechanisms underlying cell death activation by such compounds in this cell type have not been fully elucidated. In this work, we attempted to reconstitute the key pathways and master regulators involved in the response of human cervical carcinoma KB-3-1 cells to the novel glycyrrhetinic acid derivative soloxolone methyl (SM) by a transcriptomic approach. Functional annotation of differentially expressed genes, analysis of their cis- regulatory sequences and protein-protein interaction network clearly indicated that stress of endoplasmic reticulum (ER) is the central event triggered by SM in the cells. A range of key ER stress sensors and transcription factor AP-1 were identified as upstream transcriptional regulators, controlling the response of the cells to SM. Additionally, by using Gene Expression Omnibus data, we showed the ability of SM to modulate the expression of key genes involved in regulation of the high proliferative rate of cervical carcinoma cells. Further Connectivity Map analysis revealed similarity of SM's effects with known ER stress inducers thapsigargin and geldanamycin, targeting SERCA and Grp94, respectively. According to the molecular docking study, SM could snugly fit into the active sites of these proteins in the positions very close to that of both inhibitors. Taken together, our findings provide a basis for the better understanding of the intracellular processes in tumor cells switched on in response to cyano enone-bearing triterpenoids. |
| Databáze: | OpenAIRE |
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