Different signaling and functionality of Rac1 and Rac1b in the progression of lung adenocarcinoma.

Publisher: Walter De Gruyter Country of Publication: Germany NLM ID: 9700112 Publication Model: Print Cited Medium: Internet ISSN: 1437-4315 (Electronic) Linking ISSN: 14316730 NLM ISO Abbreviation: Biol Chem Subsets: MEDLINE

Publication: Berlin : Walter De Gruyter
Original Publication: Berlin ; New York : W. De Gruyter, c1996-

Carcinoma, Non-Small-Cell Lung/*metabolism ; Lung Neoplasms/*metabolism ; rac1 GTP-Binding Protein/*metabolism; Carcinoma, Non-Small-Cell Lung/pathology ; Epithelial-Mesenchymal Transition/genetics ; Humans ; Lung Neoplasms/pathology ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; Signal Transduction/genetics ; Tumor Cells, Cultured ; rac1 GTP-Binding Protein/analysis ; rac1 GTP-Binding Protein/genetics

Rac1 is a ubiquitously expressed Rho GTPase and an important regulator of the actin cytoskeleton. Its splice variant Rac1b exhibits a 19-amino acid (aa) in-frame insertion and is predominantly active. Both proteins were described in tumorigenesis or metastasis. We investigated the contribution of Rac1 and Rac1b to tumor progression of human non-small-cell lung adenocarcinoma (NSCLA). Rac1 protein was present in 8/8 NSCLA cell lines analyzed, whereas Rac1b was expressed in only 6/8. In wound-healing assays, enhanced green fluorescence protein (EGFP)-Rac1 slightly decreased cell migration, whereas proliferation was increased in both, Rac1- and Rac1b-expressing cells. In the in vivo chorioallantoic invasion model, EGFP-Rac1-expressing cells formed more invasive tumors compared to EGFP-Rac1b. This increased invasiveness correlated with enhanced phosphorylation of p38α, AKT and glycogen synthase kinase 3β (GSK3β), and activation of serum response- and Smad-dependent gene promoters by Rac1. In contrast, Rac1b solely activated the mitogen-activated protein kinase (MAPK) JNK2, together with TCF/LEF1- and nuclear factor kappa B (NFκB)-responsive gene reporters. Rac1b, as Rac1, phosphorylated p38α, AKT and GSK3β. Knockdown of the splicing factor epithelial splicing regulatory protein 1 (ESRP1), which mediates out-splicing of exon 3b from Rac1 pre-messenger RNA, resulted in increased Rac1b messenger RNA (mRNA) and suppression of the epithelial-mesenchymal transition (EMT)-associated transcription factor ZEB1. Our data demonstrate different signaling and functional activities of Rac1 and Rac1b and an important role for Rac1 in lung cancer metastasis.

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Keywords: NSCLC; Rac1 signaling; Rho GTPases; cell migration; epithelial-to-mesenchymal transition; lung cancer metastasis; tumor invasion

0 (RAC1 protein, human)
0 (RNA, Messenger)
EC 3.6.5.2 (rac1 GTP-Binding Protein)

Date Created: 20191208 Date Completed: 20210624 Latest Revision: 20221026

20221213

10.1515/hsz-2019-0329

31811797