Adducins inhibit lung cancer cell migration through mechanisms involving regulation of cell-matrix adhesion and cadherin-11 expression

Susana Lechuga, Parth H. Amin, Aaron Wolen, Andrei I. Ivanov

Research output: Contribution to journalArticle

Abstract

Cell migration is a critical mechanism controlling tissue morphogenesis, epithelial wound healing and tumor metastasis. Migrating cells depend on orchestrated remodeling of the plasma membrane and the underlying actin cytoskeleton, which is regulated by the spectrin-adducin-based membrane skeleton. Expression of adducins is altered during tumorigenesis, however, their involvement in metastatic dissemination of tumor cells remains poorly characterized. This study investigated the roles of α-adducin (ADD1) and γ-adducin (ADD3) in regulating migration and invasion of non-small cell lung cancer (NSCLC) cells. ADD1 was mislocalized, whereas ADD3 was markedly downregulated in NSCLC cells with the invasive mesenchymal phenotype. CRISPR/Cas9-mediated knockout of ADD1 and ADD3 in epithelial-type NSCLC and normal bronchial epithelial cells promoted their Boyden chamber migration and Matrigel invasion. Furthermore, overexpression of ADD1, but not ADD3, in mesenchymal-type NSCLC cells decreased cell migration and invasion. ADD1-overexpressing NSCLC cells demonstrated increased adhesion to the extracellular matrix (ECM), accompanied by enhanced assembly of focal adhesions and hyperphosphorylation of Src and paxillin. The increased adhesiveness and decreased motility of ADD1-overexpressing cells were reversed by siRNA-mediated knockdown of Src. By contrast, the accelerated migration of ADD1 and ADD3-depleted NSCLC cells was ECM adhesion-independent and was driven by the upregulated expression of pro-motile cadherin-11. Overall, our findings reveal a novel function of adducins as negative regulators of NSCLC cell migration and invasion, which could be essential for limiting lung cancer progression and metastasis.

Original languageEnglish (US)
Pages (from-to)395-408
Number of pages14
JournalBiochimica et Biophysica Acta - Molecular Cell Research
Volume1866
Issue number3
DOIs
StatePublished - Mar 1 2019

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Cell-Matrix Junctions
Cell Movement
Non-Small Cell Lung Carcinoma
Lung Neoplasms
Extracellular Matrix
Clustered Regularly Interspaced Short Palindromic Repeats
Paxillin
Neoplasm Metastasis
Adhesiveness
Spectrin
Focal Adhesions
adducin
osteoblast cadherin
Actin Cytoskeleton
Morphogenesis
Skeleton
Wound Healing
Small Interfering RNA
Neoplasms
Carcinogenesis

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

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Adducins inhibit lung cancer cell migration through mechanisms involving regulation of cell-matrix adhesion and cadherin-11 expression. / Lechuga, Susana; Amin, Parth H.; Wolen, Aaron; Ivanov, Andrei I.

In: Biochimica et Biophysica Acta - Molecular Cell Research, Vol. 1866, No. 3, 01.03.2019, p. 395-408.

Research output: Contribution to journalArticle

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