Translocation of LSR from tricellular corners causes macropinocytosis at cell–cell interface as a trigger for breaking out of contact inhibition

Abstract

Withdrawal from contact inhibition is necessary for epithelial cancer precursor cells to initiate cell growth and motility. Nevertheless, little is understood about the mechanism for the sudden initiation of cell growth under static conditions. We focused on cellular junctions as one region where breaking out of contact inhibition occurs. In well‐differentiated endometrial cancer cells, Sawano, the ligand administration for tricellular tight junction protein LSR, which transiently decreased the robust junction property, caused an abrupt increase in cell motility and consequent excessive multilayered cell growth despite being under contact inhibition conditions. We observed that macropinocytosis essentially and temporarily occurred as an antecedent event for the above process at intercellular junctions without disruption of the junction apparatus but not at the apical plasma membrane. Collectively, we concluded that the formation of macropinocytosis, which is derived from tight junction‐mediated signaling, was triggered for the initiation of cell growth in static precancerous epithelium.

Atypical Macropinocytosis Contributes to Malignant Progression: A Review of Recent Evidence in Endometrioid Endometrial Cancer Cells

“…These processes involve the activation of the RhoG-Rac pathway and reorganization of actin filaments [ 35 ]. Recently, it was reported that macropinocytosis is necessary for breaking out contact inhibition and initiating stratified cell growth in well-differentiated human endometrial cancer cells ( Figure 1 ) [ 4 ]. While macropinocytosis, which is Rac-dependent, occurs through the temporary split of adjacent cell junctions; there is no protrusion of the cell membrane prior to macropinocytosis.…”

“…Sawano cell was established by endometrial adenocarcinoma of uterus [ 63 ]. Sawano has a KRAS G13D heterozygous mutation and wild-type BRaf [ 4 ]. According to this study, Sawano cells have high planar motility at low cell densities, whereas at high cell densities, their growth and motility are temporarily arrested due to contact inhibition.…”

“…In bovine retinal endothelial cells (BRECs), OCLN is phosphorylated and ubiquitinated 30 min after VEGF stimulation and translocates from tight junctions to early and late endosomes [ 107 ]. LSR is excluded from tricellular tight junctions by LSR ligand stimulation, and LSR subsequently colocalizes with Rab5-positive vesicles at bicellular junctions [ 4 ]. The pathway by which the LSR translocates from the bicellular region to the intracellular region and the mechanism by which the intracellularly translocated LSR is recycled to the junction region is unclear.…”

“…Hence, Kondoh et al established an experimental system that enables the simultaneous reduction of LSR expression in all areas of cultured cells using LSR ligands [ 108 ]. Administration of the LSR ligand to Sawano cells induces LSR localized in tricellular tight junctions into Rab5-positive intracellular vesicles via bicellular junctions [ 4 ]. Under these conditions, the LSR ligand transiently reduced epithelial barrier function, but it had little effect on OCLN expression and localization and did not completely disrupt epithelial barrier function.…”

“…In cancer cells, high macropinocytosis activity is used as a supply pathway of amino acids required for cell proliferation [ 3 ]. A recent study identified a new role for macropinocytosis, inducing the initiation of malignant progression of endometrial cancer cells [ 4 ]. Macropinocytosis is attributed to the disruption of epithelial cell homeostasis.…”