The anti-tumor effect of trifluridine via induction of aberrant mitosis is unaffected by mutations modulating p53 activity.
Journal
Cell death discovery
ISSN: 2058-7716
Titre abrégé: Cell Death Discov
Pays: United States
ID NLM: 101665035
Informations de publication
Date de publication:
02 Jul 2024
02 Jul 2024
Historique:
received:
13
03
2024
accepted:
21
06
2024
revised:
18
06
2024
medline:
3
7
2024
pubmed:
3
7
2024
entrez:
2
7
2024
Statut:
epublish
Résumé
The fluorinated thymidine analog trifluridine (FTD) is a chemotherapeutic drug commonly used to treat cancer; however, the mechanism by which FTD induces cytotoxicity is not fully understood. In addition, the effect of gain-of-function (GOF) missense mutations of the TP53 gene (encoding p53), which promote cancer progression and chemotherapeutic drug resistance, on the chemotherapeutic efficacy of FTD is unclear. Here, we revealed the mechanisms by which FTD-induced aberrant mitosis and contributed to cytotoxicity in both p53-null and p53-GOF missense mutant cells. In p53-null mutant cells, FTD-induced DNA double-stranded breaks, single-stranded DNA accumulation, and the associated DNA damage responses during the G2 phase. Nevertheless, FTD-induced DNA damage and the related responses were not sufficient to trigger strict G2/M checkpoint arrest. Thus, these features were carried over into mitosis, resulting in chromosome breaks and bridges, and subsequent cytokinesis failure. Improper mitotic exit eventually led to cell apoptosis, caused by the accumulation of extensive DNA damage and the presence of micronuclei encapsulated in the disrupted nuclear envelope. Upon FTD treatment, the behavior of the p53-GOF-missense mutant, isogenic cell lines, generated by CRISPR/Cas9 genome editing, was similar to that of p53-null mutant cells. Thus, our data suggest that FTD treatment overrode the effect on gene expression induced by p53-GOF mutants and exerted its anti-tumor activity in a manner that was independent of the p53 function.
Identifiants
pubmed: 38956056
doi: 10.1038/s41420-024-02083-3
pii: 10.1038/s41420-024-02083-3
doi:
Types de publication
Journal Article
Langues
eng
Pagination
307Subventions
Organisme : MEXT | Japan Society for the Promotion of Science (JSPS)
ID : 22K19577
Organisme : MEXT | Japan Society for the Promotion of Science (JSPS)
ID : 23K24030
Informations de copyright
© 2024. The Author(s).
Références
Galmarini CM, Mackey JR, Dumontet C. Nucleoside analogues and nucleobases in cancer treatment. Lancet Oncol. 2002;3:415–24.
pubmed: 12142171
doi: 10.1016/S1470-2045(02)00788-X
Kitao H, Iimori M, Kataoka Y, Wakasa T, Tokunaga E, Saeki H, et al. DNA replication stress and cancer chemotherapy. Cancer Sci. 2018;109:264–71.
pubmed: 29168596
doi: 10.1111/cas.13455
Shitara K, Doi T, Dvorkin M, Mansoor W, Arkenau HT, Prokharau A, et al. Trifluridine/tipiracil versus placebo in patients with heavily pretreated metastatic gastric cancer (TAGS): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2018;19:1437–48.
pubmed: 30355453
doi: 10.1016/S1470-2045(18)30739-3
Mayer RJ, Van Cutsem E, Falcone A, Yoshino T, Garcia-Carbonero R, Mizunuma N, et al. Randomized trial of TAS-102 for refractory metastatic colorectal cancer. N Engl J Med. 2015;372:1909–19.
pubmed: 25970050
doi: 10.1056/NEJMoa1414325
Prager GW, Taieb J, Fakih M, Ciardiello F, Van Cutsem E, Elez E, et al. Trifluridine-tipiracil and bevacizumab in refractory metastatic colorectal cancer. N Engl J Med. 2023;388:1657–67.
pubmed: 37133585
doi: 10.1056/NEJMoa2214963
Kataoka Y, Iimori M, Niimi S, Tsukihara H, Wakasa T, Saeki H, et al. Cytotoxicity of trifluridine correlates with the thymidine kinase 1 expression level. Sci Rep. 2019;9:7964.
pubmed: 31138881
pmcid: 6538667
doi: 10.1038/s41598-019-44399-6
Kataoka Y, Iimori M, Fujisawa R, Morikawa-Ichinose T, Niimi S, Wakasa T, et al. DNA replication stress induced by trifluridine determines tumor cell fate according to p53 status. Mol Cancer Res MCR. 2020;18:1354–66.
pubmed: 32467171
doi: 10.1158/1541-7786.MCR-19-1051
Kitao H, Morodomi Y, Niimi S, Kiniwa M, Shigeno K, Matsuoka K, et al. The antibodies against 5-bromo-2’-deoxyuridine specifically recognize trifluridine incorporated into DNA. Sci Rep. 2016;6:25286.
pubmed: 27137226
pmcid: 4853717
doi: 10.1038/srep25286
Bijnsdorp IV, Kruyt FA, Fukushima M, Peters GJ. Trifluorothymidine induces cell death independently of p53. Nucleosides Nucleotides Nucleic Acids. 2008;27:699–703.
pubmed: 18600528
doi: 10.1080/15257770802145017
de Andrade KC, Lee EE, Tookmanian EM, Kesserwan CA, Manfredi JJ, Hatton JN, et al. The TP53 Database: transition from the International Agency for Research on Cancer to the US National Cancer Institute. Cell Death Differ. 2022;29:1071–3.
pubmed: 35352025
pmcid: 9090805
doi: 10.1038/s41418-022-00976-3
Bullock AN, Fersht AR. Rescuing the function of mutant p53. Nat Rev Cancer. 2001;1:68–76.
pubmed: 11900253
doi: 10.1038/35094077
Freed-Pastor WA, Mizuno H, Zhao X, Langerod A, Moon SH, Rodriguez-Barrueco R, et al. Mutant p53 disrupts mammary tissue architecture via the mevalonate pathway. Cell. 2012;148:244–58.
pubmed: 22265415
pmcid: 3511889
doi: 10.1016/j.cell.2011.12.017
Lozano G, Zambetti GP. What have animal models taught us about the p53 pathway? J Pathol. 2005;205:206–20.
pubmed: 15643668
doi: 10.1002/path.1704
Zhang C, Liu J, Liang Y, Wu R, Zhao Y, Hong X, et al. Tumour-associated mutant p53 drives the Warburg effect. Nat Commun. 2013;4:2935.
pubmed: 24343302
doi: 10.1038/ncomms3935
Weissmueller S, Manchado E, Saborowski M, Morris JP 4th, Wagenblast E, Davis CA, et al. Mutant p53 drives pancreatic cancer metastasis through cell-autonomous PDGF receptor beta signaling. Cell. 2014;157:382–94.
pubmed: 24725405
pmcid: 4001090
doi: 10.1016/j.cell.2014.01.066
Muller PA, Vousden KH, Norman JC. p53 and its mutants in tumor cell migration and invasion. J Cell Biol. 2011;192:209–18.
pubmed: 21263025
pmcid: 3172183
doi: 10.1083/jcb.201009059
Huang Y, Liu N, Liu J, Liu Y, Zhang C, Long S, et al. Mutant p53 drives cancer chemotherapy resistance due to loss of function on activating transcription of PUMA. Cell Cycle. 2019;18:3442–55.
pubmed: 31726940
pmcid: 6927701
doi: 10.1080/15384101.2019.1688951
Do PM, Varanasi L, Fan S, Li C, Kubacka I, Newman V, et al. Mutant p53 cooperates with ETS2 to promote etoposide resistance. Genes Dev. 2012;26:830–45.
pubmed: 22508727
pmcid: 3337457
doi: 10.1101/gad.181685.111
Perego P, Giarola M, Righetti SC, Supino R, Caserini C, Delia D, et al. Association between cisplatin resistance and mutation of p53 gene and reduced bax expression in ovarian carcinoma cell systems. Cancer Res. 1996;56:556–62.
pubmed: 8564971
Lee JM, Bernstein A. p53 mutations increase resistance to ionizing radiation. Proc Natl Acad Sci USA. 1993;90:5742–6.
pubmed: 8516323
pmcid: 46798
doi: 10.1073/pnas.90.12.5742
Shu S, Iimori M, Wakasa T, Ando K, Saeki H, Oda Y, et al. The balance of forces generated by kinesins controls spindle polarity and chromosomal heterogeneity in tetraploid cells. J Cell Sci. 2019;132:jcs231530.
pubmed: 31757888
doi: 10.1242/jcs.231530
Sakaue-Sawano A, Kurokawa H, Morimura T, Hanyu A, Hama H, Osawa H, et al. Visualizing spatiotemporal dynamics of multicellular cell-cycle progression. Cell. 2008;132:487–98.
pubmed: 18267078
doi: 10.1016/j.cell.2007.12.033
Grant GD, Kedziora KM, Limas JC, Cook JG, Purvis JE. Accurate delineation of cell cycle phase transitions in living cells with PIP-FUCCI. Cell Cycle. 2018;17:2496–516.
pubmed: 30421640
pmcid: 6342071
doi: 10.1080/15384101.2018.1547001
Chan YW, Fugger K, West SC. Unresolved recombination intermediates lead to ultra-fine anaphase bridges, chromosome breaks and aberrations. Nat Cell Biol. 2018;20:92–103.
pubmed: 29255170
doi: 10.1038/s41556-017-0011-1
Minocherhomji S, Ying S, Bjerregaard VA, Bursomanno S, Aleliunaite A, Wu W, et al. Replication stress activates DNA repair synthesis in mitosis. Nature. 2015;528:286–90.
pubmed: 26633632
doi: 10.1038/nature16139
Hatch EM, Fischer AH, Deerinck TJ, Hetzer MW. Catastrophic nuclear envelope collapse in cancer cell micronuclei. Cell. 2013;154:47–60.
pubmed: 23827674
pmcid: 3749778
doi: 10.1016/j.cell.2013.06.007
Cho Y, Gorina S, Jeffrey PD, Pavletich NP. Crystal structure of a p53 tumor suppressor-DNA complex: understanding tumorigenic mutations. Science. 1994;265:346–55.
pubmed: 8023157
doi: 10.1126/science.8023157
el-Deiry WS, Tokino T, Velculescu VE, Levy DB, Parsons R, Trent JM, et al. WAF1, a potential mediator of p53 tumor suppression. Cell. 1993;75:817–25.
pubmed: 8242752
doi: 10.1016/0092-8674(93)90500-P
Zhu J, Sammons MA, Donahue G, Dou Z, Vedadi M, Getlik M, et al. Gain-of-function p53 mutants co-opt chromatin pathways to drive cancer growth. Nature. 2015;525:206–11.
pubmed: 26331536
pmcid: 4568559
doi: 10.1038/nature15251
Matsuoka K, Iimori M, Niimi S, Tsukihara H, Watanabe S, Kiyonari S, et al. Trifluridine induces p53-dependent sustained G2 phase arrest with its massive misincorporation into DNA and few DNA strand breaks. Mol Cancer Ther. 2015;14:1004–13.
pubmed: 25700705
doi: 10.1158/1535-7163.MCT-14-0236
Cybulla E, Vindigni A. Leveraging the replication stress response to optimize cancer therapy. Nat Rev Cancer. 2023;23:6–24.
pubmed: 36323800
doi: 10.1038/s41568-022-00518-6
Saldivar JC, Cortez D, Cimprich KA. The essential kinase ATR: ensuring faithful duplication of a challenging genome. Nat Rev Mol Cell Biol. 2017;18:622–36.
pubmed: 28811666
pmcid: 5796526
doi: 10.1038/nrm.2017.67
Ragland RL, Patel S, Rivard RS, Smith K, Peters AA, Bielinsky AK, et al. RNF4 and PLK1 are required for replication fork collapse in ATR-deficient cells. Genes Dev. 2013;27:2259–73.
pubmed: 24142876
pmcid: 3814646
doi: 10.1101/gad.223180.113
Couch FB, Bansbach CE, Driscoll R, Luzwick JW, Glick GG, Betous R, et al. ATR phosphorylates SMARCAL1 to prevent replication fork collapse. Genes Dev. 2013;27:1610–23.
pubmed: 23873943
pmcid: 3731549
doi: 10.1101/gad.214080.113
Toledo LI, Altmeyer M, Rask MB, Lukas C, Larsen DH, Povlsen LK, et al. ATR prohibits replication catastrophe by preventing global exhaustion of RPA. Cell. 2013;155:1088–103.
pubmed: 24267891
doi: 10.1016/j.cell.2013.10.043
Boteva L, Nozawa RS, Naughton C, Samejima K, Earnshaw WC, Gilbert N. Common fragile sites are characterized by faulty condensin loading after replication stress. Cell Rep. 2020;32:108177.
pubmed: 32966795
pmcid: 7511797
doi: 10.1016/j.celrep.2020.108177
Wechsler T, Newman S, West SC. Aberrant chromosome morphology in human cells defective for Holliday junction resolution. Nature. 2011;471:642–6.
pubmed: 21399624
pmcid: 3560329
doi: 10.1038/nature09790
Kawamoto T, Araki K, Sonoda E, Yamashita YM, Harada K, Kikuchi K, et al. Dual roles for DNA polymerase eta in homologous DNA recombination and translesion DNA synthesis. Mol Cell. 2005;20:793–9.
pubmed: 16337602
doi: 10.1016/j.molcel.2005.10.016
Grandbois M, Beyer M, Rief M, Clausen-Schaumann H, Gaub HE. How strong is a covalent bond? Science. 1999;283:1727–30.
pubmed: 10073936
doi: 10.1126/science.283.5408.1727
Alexander SP, Rieder CL. Chromosome motion during attachment to the vertebrate spindle: initial saltatory-like behavior of chromosomes and quantitative analysis of force production by nascent kinetochore fibers. J Cell Biol. 1991;113:805–15.
pubmed: 2026651
doi: 10.1083/jcb.113.4.805
Mackenzie KJ, Carroll P, Martin CA, Murina O, Fluteau A, Simpson DJ, et al. cGAS surveillance of micronuclei links genome instability to innate immunity. Nature. 2017;548:461–5.
pubmed: 28738408
pmcid: 5870830
doi: 10.1038/nature23449
Ding L, Kim HJ, Wang Q, Kearns M, Jiang T, Ohlson CE, et al. PARP inhibition elicits STING-dependent antitumor immunity in Brca1-deficient ovarian cancer. Cell Rep. 2018;25:2972–80.e2975.
pubmed: 30540933
pmcid: 6366450
doi: 10.1016/j.celrep.2018.11.054
Maciejowski J, de Lange T. Telomeres in cancer: tumour suppression and genome instability. Nat Rev Mol Cell Biol. 2017;18:175–86.
pubmed: 28096526
pmcid: 5589191
doi: 10.1038/nrm.2016.171
Rucker FG, Dolnik A, Blatte TJ, Teleanu V, Ernst A, Thol F, et al. Chromothripsis is linked to TP53 alteration, cell cycle impairment, and dismal outcome in acute myeloid leukemia with complex karyotype. Haematologica. 2018;103:e17–e20.
pubmed: 29079594
pmcid: 5777208
doi: 10.3324/haematol.2017.180497
Fontana MC, Marconi G, Feenstra JDM, Fonzi E, Papayannidis C, Ghelli Luserna di Rora A, et al. Chromothripsis in acute myeloid leukemia: biological features and impact on survival. Leukemia. 2018;32:1609–20.
pubmed: 29472722
pmcid: 6035145
doi: 10.1038/s41375-018-0035-y
Naito Y, Hino K, Bono H, Ui-Tei K. CRISPRdirect: software for designing CRISPR/Cas guide RNA with reduced off-target sites. Bioinformatics. 2015;31:1120–3.
pubmed: 25414360
doi: 10.1093/bioinformatics/btu743
Hashimshony T, Senderovich N, Avital G, Klochendler A, de Leeuw Y, Anavy L, et al. CEL-Seq2: sensitive highly-multiplexed single-cell RNA-Seq. Genome Biol. 2016;17:77.
pubmed: 27121950
pmcid: 4848782
doi: 10.1186/s13059-016-0938-8
Miyawaki-Kuwakado A, Wu Q, Harada A, Tomimatsu K, Fujii T, Maehara K, et al. Transcriptome analysis of gene expression changes upon enzymatic dissociation in skeletal myoblasts. Genes Cells. 2021;26:530–40.
pubmed: 33987903
doi: 10.1111/gtc.12870
Benjamini Y, Hochberg Y. Controlling the false discovery rate - a practical and powerful approach to multiple testing. J R Stat Soc B. 1995;57:289–300.
doi: 10.1111/j.2517-6161.1995.tb02031.x
Sherman BT, Hao M, Qiu J, Jiao X, Baseler MW, Lane HC, et al. DAVID: a web server for functional enrichment analysis and functional annotation of gene lists (2021 update). Nucleic Acids Res. 2022;50:W216–W221.
pubmed: 35325185
pmcid: 9252805
doi: 10.1093/nar/gkac194
Iimori M, Watanabe S, Kiyonari S, Matsuoka K, Sakasai R, Saeki H, et al. Phosphorylation of EB2 by Aurora B and CDK1 ensures mitotic progression and genome stability. Nat Commun. 2016;7:11117.
pubmed: 27030108
pmcid: 4821873
doi: 10.1038/ncomms11117