Khromova Natalia, Vasileva Maria, Dugina Vera, Kudlay Dmitry, Chumakov Peter, Boichuk Sergei, Kopnin Pavel
Carcinogenesis Institute, N.N. Blokhin National Medical Research Oncology Center, The Ministry of Health of Russia, 115478 Moscow, Russia.
Belozersky Research Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119992 Moscow, Russia.
Cancers (Basel). 2024 Mar 11;16(6):1123. doi: 10.3390/cancers16061123.
Cancer cell aggressiveness, marked by actin cytoskeleton reconfiguration critical for metastasis, may result from an imbalanced ratio favoring γ-actin. Dysfunctional p53 emerges as a key regulator of invasiveness and migration in various cancer cells, both in vitro and in vivo. P53 inactivation (via mutants R175H, R248W, R273H, or TP53 repression) significantly enhanced the migration, invasion, and proliferation of human lung adenocarcinoma A549 cells in vitro and in vivo, facilitating intrapulmonary xenograft metastasis in athymic mice. Conversely, wild-type TP53 (TP53 WT) overexpression in p53-deficient non-small- cell lung cancer (NSCLC) H1299 cells substantially reduced proliferation and migration in vitro, effectively curbing orthotopic tumorigenicity and impeding in vivo metastasis. These alterations in cell motility were closely associated with actin cytoskeleton restructuring, favoring γ-actin, and coincided with ERK1/2-mediated signaling activation, unveiling an innovative regulatory mechanism in malignancy progression. Cancer cell aggressiveness, driven by actin cytoskeleton reorganization and a shift towards γ-actin predominance, may be regulated by p53 dysfunction, thereby providing novel insight into tumor progression mechanisms.
癌细胞的侵袭性以对转移至关重要的肌动蛋白细胞骨架重构为特征，这可能是由于有利于γ-肌动蛋白的比例失衡所致。功能失调的p53在体外和体内均成为各种癌细胞侵袭和迁移的关键调节因子。p53失活（通过R175H、R248W、R273H突变体或TP53抑制）在体外和体内均显著增强了人肺腺癌A549细胞的迁移、侵袭和增殖，促进了无胸腺小鼠肺内异种移植转移。相反，在p53缺陷的非小细胞肺癌（NSCLC）H1299细胞中过表达野生型TP53（TP53 WT）可显著降低体外增殖和迁移，有效抑制原位致瘤性并阻碍体内转移。细胞运动性的这些改变与有利于γ-肌动蛋白的肌动蛋白细胞骨架重组密切相关，并且与ERK1/2介导的信号激活同时发生，揭示了恶性肿瘤进展中的一种创新调节机制。由肌动蛋白细胞骨架重组和向γ-肌动蛋白优势转变驱动的癌细胞侵袭性可能受p53功能障碍调节，从而为肿瘤进展机制提供了新的见解。
