Deep insights into the response of human cervical carcinoma cells to a new cyano enone-bearing triterpenoid soloxolone methyl: A transcriptome analysis

Deep insights into the response of human cervical carcinoma cells to a new cyano enone-bearing triterpenoid soloxolone methyl: A transcriptome analysis Full article

Journal

Oncotarget
ISSN: 1949-2553

Output data

Year: 2019, Volume: 10, Number: 51, Pages: 5267-5297 Pages count : 31 DOI: 10.18632/oncotarget.27085

Tags

CDDO-Me; Cervical carcinoma; Cytoscape; Mechanism of action; Soloxolone methyl

Authors

Markov A.V. ¹ , Kel A.E. ^1,2 , Salomatina O.V. ^1,3 , Salakhutdinov N.F. ³ , Zenkova M.A. ¹ , Logashenko E.B. ¹

Affiliations

1	(Scopus) Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, 630090, Russian Federation
2	(Scopus) GeneXplain GmbH, Wolfenb?ttel, 38302, Germany
3	(Scopus) N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, 630090, Russian Federation

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. © 2019 Markov et al.

Markov A.V. , Kel A.E. , Salomatina O.V. , Salakhutdinov N.F. , Zenkova M.A. , Logashenko E.B.
Deep insights into the response of human cervical carcinoma cells to a new cyano enone-bearing triterpenoid soloxolone methyl: A transcriptome analysis

Oncotarget. 2019. V.10. N51. P.5267-5297. DOI: 10.18632/oncotarget.27085 Scopus РИНЦ

Full text from publisher

Published print:	Sep 3, 2019
Published online:	Sep 3, 2019

Scopus	2-s2.0-85072035522
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OpenAlex	W2975309110