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Therapy-induced stress response is associated with downregulation of pre-mRNA
splicing in cancer cells
#MMPMID29950180
Anufrieva KS
; Shender V?
; Arapidi GP
; Pavlyukov MS
; Shakhparonov MI
; Shnaider PV
; Butenko IO
; Lagarkova MA
; Govorun VM
Genome Med
2018[Jun]; 10
(1
): 49
PMID29950180
show ga
BACKGROUND: Abnormal pre-mRNA splicing regulation is common in cancer, but the
effects of chemotherapy on this process remain unclear. METHODS: To evaluate the
effect of chemotherapy on slicing regulation, we performed meta-analyses of
previously published transcriptomic, proteomic, phosphoproteomic, and secretome
datasets. Our findings were verified by LC-MS/MS, western blotting,
immunofluorescence, and FACS analyses of multiple cancer cell lines treated with
cisplatin and pladienolide B. RESULTS: Our results revealed that different types
of chemotherapy lead to similar changes in alternative splicing by inducing
intron retention in multiple genes. To determine the mechanism underlying this
effect, we analyzed gene expression in 101 cell lines affected by ?-irradiation,
hypoxia, and 10 various chemotherapeutic drugs. Strikingly, ?nly genes involved
in the cell cycle and pre-mRNA splicing regulation were changed in a similar
manner in all 335 tested samples regardless of stress stimuli. We revealed
significant downregulation of gene expression levels in these two pathways, which
could be explained by the observed decrease in splicing efficiency and global
intron retention. We showed that the levels of active spliceosomal proteins might
be further post-translationally decreased by phosphorylation and export into the
extracellular space. To further explore these bioinformatics findings, we
performed proteomic analysis of cisplatin-treated ovarian cancer cells. Finally,
we demonstrated that the splicing inhibitor pladienolide B impairs the cellular
response to DNA damage and significantly increases the sensitivity of cancer
cells to chemotherapy. CONCLUSIONS: Decreased splicing efficiency and global
intron retention is a novel stress response mechanism that may promote survival
of malignant cells following therapy. We found that this mechanism can be
inhibited by pladienolide B, which significantly increases the sensitivity of
cancer cells to cisplatin which makes it a good candidate drug for improving the
efficiency of cancer therapy.
|Antineoplastic Agents/pharmacology/therapeutic use
[MESH]
|Cell Cycle/drug effects/genetics
[MESH]
|Cell Line, Tumor
[MESH]
|Cluster Analysis
[MESH]
|DNA Damage/genetics
[MESH]
|Down-Regulation/drug effects/*genetics
[MESH]
|Epoxy Compounds/pharmacology/therapeutic use
[MESH]
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