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- W2810897738 abstract "ABSTRACT Introduction The enhancement of tumour cell malignant characteristics could be caused by a shift in the ratio of cytoplasmic actin isoforms (β- and γ-) via γ-actin increasing. We have previously shown that γ-actin predominance in neoplastic cells led to tumour progression due to ERK1/2 activation, and vice versa Ras-dependent ERK1/2 activation led to γ-actin increasing. There is probably a positive feedback loop between MAPKs activation and γ-actin level enhancing malignant traits of neoplastic cells. Since MAPKs activation was observed in many human tumours as a result of oncogenes activation and/or tumour suppressors inactivation, it has been important to identify mechanisms that lead to a shift in the ratio of β-/γ- actin. We aimed to study neoplastic cell properties caused by tumour suppressor p53 dysfunction: changes in cytoskeleton, motility, growth rates in vitro and in vivo, metastasis, as well as to identify the molecular mechanisms underlying these changes. Material and methods We created A549 derivatives expressing exogenous mutant p53 proteins with amino-acid substitutions at positions 175, 248, 273 representing hot-spot mutations, and the subline with TP53 repression induced by shRNAs as well as H1299 cells with both deleted TP53 alleles with exogenous-restored wild type p53 expression. Results and discussions Inactivation of normal p53 function by exogenous mutant forms with known dominant-negative effect, as well as the TP53 repression in A549 cells led to increased migration and invasion, proliferation, the growth rate of subcutaneous xenografts as well as increased metastasis of intrapulmonary A549 xenografts in nude mice. Exogenous TP53 WT expression in p53-negative cells H1299, on the contrary, suppressed proliferation and migration, significantly reduced orthotopic tumorigenicity and metastasis. The change in cell motility was associated with actin cytoskeleton reorganisation and shift in the actin isoforms ratio. Apparently, the shift in the ratio towards γ-actin predominance occurred as a result of ERK1/2 activation in cells with p53 dysfunction and led to enhanced neoplastic cell malignant properties. Conclusion Actin cytoskeleton reorganisation via increasing γ-actin level stimulated tumour progression and metastasis as a result of tumour suppressor p53 dysfunction and activation of MAPKs so γ-actin predominance could be a universal characteristic of neoplastic cells. The study was supported Russian Science Foundation (RSCF), grant No. 14-15-00467." @default.
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- W2810897738 date "2018-06-01" @default.
- W2810897738 modified "2023-10-02" @default.
- W2810897738 title "PO-232 Actin-dependent effect of tumour suppressor P53 on human lung cancer cell malignant characteristics" @default.
- W2810897738 doi "https://doi.org/10.1136/esmoopen-2018-eacr25.749" @default.
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