- The 6-h samples showed activation of the cell cycle inhibitor CDKN1A which might be involved in the secondary response in 12-h samples.. - This secondary response predominantly consisted of cell cycle-related changes, with further activation of CDKN1A and inhibition of the transcription factor E2F1 , including downstream target genes, resulting in G1-phase arrest.. - Conclusions: FX-9 induced G1-phase arrest of PC-3 cells through activation of the cell cycle inhibitor CDKN1A , which was initiated by an inflammatory response of noncanonical NF- κ B signaling.. - To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.. - The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.. - Antimitotic drugs disrupt the cell cycle progression of tumor cells. - The purpose of the cell cycle is to du- plicate the DNA accurately and to segregate the cop- ies into two identical daughter cells. - In brief, the cell cycle is divided into G1-phase, S-phase, G2-phase and M-phase. - If a checkpoint is activated, for example, due to DNA damage, the cell cycle is arrested until either DNA repair or programmed cell death occurs [10]. - It develops in 10–20% of patients with prostate cancer where androgen deprivation therapy has failed [17]. - FX-9 induced Reactome-pathways of the immune system after 6-h exposure and in cell cycle pathways after 12-h exposure. - Two signaling pathways of the super- pathway “ cell cycle ” were enriched by upregulation of CDKN1A (FC 3.88, Fig. - The pathway “ TP53 regulates transcription of genes involved in G1 cell cycle arrest ” belongs to the superpathway gene expression, describes the involvement of genes in G1-phase cell cycle arrest and was enriched by activation of E2F7 (FC 2.56). - Seven signaling pathways assigned to the superpathway “cell cycle” were enriched by DEGs.. - The two pathways be- longing to the superpathway “gene expression” are also involved in the cell cycle. - The signaling pathways “DNA replication” and “tran- scriptional regulation of granulopoiesis” were enriched by DEGs similar to those in the superpathway “cell cycle”. - In the superpathway “RNA metabolism”, the sig- naling pathway “Insulin-like Growth Factor-2 mRNA Binding Proteins (IGF2BPs/IMPs/VICKZs) bind RNA”. - FX-9 induced time-dependent differences in the biological processes of inflammatory response and G1/S transition of mitotic cell cycle. - The biological processes “G1/S transition of mitotic cell cycle” and “positive regulation of endothelial cell proliferation” were only enriched in the 12-h. - “G1/S transition of mi- totic cell cycle” was enriched with an FDR-value of 0.0006 by nine genes, including CDC6, CDT1, CDKN1A, CCNE2, MCM3, and MCM6.. - 6 GE TP53 Regulates Transcription of Genes Involved in G1 Cell Cycle Arrest . - 9 CC Transcriptional activation of cell cycle inhibitor p . - CC “cell cycle”, ST “signal transduction”, and CR “cellular response to external stimuli”. - and “ Cell Cycle ” after 6-h and 12-h FX-9 exposure. - Due to the enrichment of DEGs in cell cycle signaling pathways from 12-h exposure, this time point was chosen to verify the transcriptome data of CDKN1A, E2F1, SERPINE1, and NFKB2 at protein level by im- munocytochemistry. - CDKN1A is a cell cycle inhibi- tor, E2F1 is an important transcription factor for entry in the S-phase, SERPINE1 plays a role in senescence, and NFKB2 is a marker for DNA damage [23–26]. - As CDKN1A, E2F1 and NFKB2 are assigned to the signal- ing pathways “immune system” or “cell cycle”, their gene expressions were visualized in Fig. - 1 GE TP53 Regulates Transcription of Genes Involved in G1 Cell Cycle Arrest e-09. - 5 GE TP53 Regulates Transcription of Cell Cycle Genes e-06. - 6 CC Cell Cycle e-06. - 7 CC Cell Cycle Checkpoints e-06. - CC “ cell cycle. - positive regulation of angiogenesis 10 4.80E-04 9 8.40E-04. - extracellular matrix organization 10 1.40E-02 10 4.80E-03. - G1/S transition of mitotic cell cycle 9 6.00E-04. - the 12-h exposure, cell cycle disturbance. - Interestingly, the potent cell cycle inhibitor CDKN1A and transcrip- tion factor E2F7 were activated in the 6-h samples, po- tentially causing the cell cycle-related response in the 12-h samples.. - After 12-h FX-9 exposure, signaling pathways of cell cycle regulation were enriched by DEGs. - FX-9 exposure increases the cell cycle inhibitor CDKN1A, which en- codes protein p21, providing multiple functions, for ex- ample, cell cycle arrest in response to drug induced DNA-damage [35]. - Inhi- biting these can provide a G1 cell cycle arrest and suppression of DNA replication [45, 46]. - Tumor cells could escape from cell cycle arrest and re-enter the cell cycle (mitotic slippage), usually resulting in those senescent cells or cell death in the G1-phase [53]. - Specifically, the enrichment of cell cycle associated DEGs regulating the transition from G1-phase to S-phase supports the thesis of an FX-9 in- duced G1-phase arrest. - Described effects of FX-9 like in- duction of cell cycle inhibitor CDKN1A, activation of NF-κB signaling pathway and senescence can be caused by DNA damage . - 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