Сборник содержит материалы научной мультиконференции «Биотех- нология медицине будущего»

Molecular determinants of cell death triggering by semisynthetic polycyclic 
compounds: what can we learn by analysis of gene regulatory networks in silico?
Markov A.V.
1
, Kel A.E.
1,2
, Logashenko E.B.
1
, Zenkova M.A.
1
1
Institute of Chemical Biology and Fundamental Medicine SB RAS, Novosibirsk, Russia 
2
geneXplain GmbH, Wolfenbüttel, Germany
Semisynthetic triterpenoids, bearing cyano enone functionality in ring A, are being 
considered now as novel promising anti-tumor agents. Such compounds were shown to display 
strong apoptogenic effect in different tumor cell lines, effectively suppress tumor growth 
in abundant murine models and a range of them, particularly CDDO-Me and its analogs, 
are being now in clinical trials. However, despite the large-scale studies, the effects of cyano 
enone-bearing triterpenoids on cervical carcinoma cells and, moreover, mechanisms under-
lying 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 response of human cervical carcinoma KB-3-1 cells on novel glycyrrhetinic acid derivative 
soloxolone methyl (SM) by a transcriptomic approach. Gene expression profiling revealed 
that treatment of KB-3-1 cells by SM for 1-10 h caused significant change in expression of 
totally 1245 genes in comparison with untreated cells (fold change > 1.5, p<0.05). Functional 
analysis of identified differentially expressed genes (DEGs) showed high enrichment of three 
main types of pathways induced by SM in the cells, notably dysregulation of endoplasmic 
reticulum (ER) homeostasis, switching on compensatory survival mechanisms to counteract 
with the SM-induced stress, identified on early stage of SM treatment (1-4 h), and triggering 
cell death pathways on the late phase of the triterpenoid action (6-10 h). Functional annotation 
of co-expressed DEGs and analysis of cis-regulatory sequences of these genes clearly indicated 
that ER stress could be considered as central event triggered by SM in KB-3-1 cells. A range of 
ER stress pathway regulators, AP-1, C/EBP and NF-kB were identified as upstream transcrip-
tional regulators, controlling response of KB-3-1 cells to the triterpenoid. Connectivity Map 
analysis revealed similarity of SM’s gene expression profiles with those of known ER stress 
inductors 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.
This research was supported by the Russian Science Foundation (Grant № 17-75-20120) and Rus-
sian State funded budget project of ICBFM SB RAS № AAAA-A17-117020210024-8.

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Всероссийская мультиконференция с международным участием «Биотехнология – медицине будущего»
29 июня - 2 июля 2019 г., г. Новосибирск, Россия
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