Abstract
The adhesion properties of cells are involved in tumor metastasis. Although KRS at the plasma membrane is shown important for cancer metastasis, additionally to canonical roles of cytosolic KRS in protein translation, how KRS and its downstream effectors promote the metastatic migration remains unexplored. Disseminative behaviors (an earlier metastatic process) of colon cancer cell spheroids embedded in 3D collagen gels were studied with regards to cell adhesion properties, and relevance in KRS(-/+) knocked-down animal and clinical colon cancer tissues. Time-lapse imaging revealed KRS-dependent cell dissemination from the spheroids, whereas KRS-suppressed spheroids remained static due to the absence of outbound movements supported by cell-extracellular matrix (ECM) adhesion. While keeping E-cadherin at the outward disseminative cells, KRS caused integrin-involved intracellular signaling for ERK/c-Jun, paxillin, and cell-ECM adhesion-mediated signaling to modulate traction force for crawling movement. KRS-suppressed spheroids became disseminative following ERK or paxillin re-expression. The KRS-dependent intracellular signaling activities correlated with the invasiveness in clinical colon tumor tissues and in KRS(-/+) knocked-down mice tissues. Collectively, these observations indicate that KRS at the plasma membrane plays new roles in metastatic migration as a signaling inducer, and causes intracellular signaling for cancer dissemination, involving cell-cell and cell-ECM adhesion, during KRS-mediated metastasis.
Highlights
Cancer metastasis is a complex process involving multiple steps, such as dissemination from the primary tumor mass, migration, and invasion, which occur even before the intravasation processes [1]
KRS is phosphorylated at the Thr52 residue by p38MAPK, which causes it to dissociate from the cytosolic multi-tRNA synthetase complex and translocate to the plasma membrane, where it associates with and stabilizes a 67 kDa laminin receptor (p67LR) involved in migration and metastasis [6]. p67-laminin receptor (p67LR) is known to associate with integrin α6β1 [8] or α6β4 [9], which have roles in cell adhesion to the extracellular matrix (ECM) and in tumor cell invasion [10]
The observations in this study made using diverse systems in vitro cells embedded in 3D collagen I gels, KRS-/+ heterozygous mice, and clinical tumor tissues, support the notion that KRS functions together with p67LR/integrin α6β1 receptors to mediate cell dissemination from cell masses via the laminin adhesion-dependent regulation of ERK1/2 and paxillin expression and activity
Summary
Cancer metastasis is a complex process involving multiple steps, such as dissemination from the primary tumor mass, migration, and invasion, which occur even before the intravasation processes [1]. KRS appears to play regulatory roles in cell adhesion by transducing intracellular signaling to activate ERK1/2 and paxillin during cancer cell dissemination from primary tumor masses.
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