Wnt5a and CCL25 promote adult T-cell acute lymphoblastic leukemia cell migration, invasion and metastasis

Abstract

Adult T-cell acute lymphoblastic leukemia (T-ALL) is a refractory leukemia. We previously showed that CCL25/CCR9 promotes T-ALL metastasis. In the present study, we assessed the effects of CCL25 on Wnt expression and the effects of Wnt5a and CCL25 on PI3K/Akt and RhoA activation. Transwell assays and mouse xenograft experiments were utilized to assess the effects of Wnt5a and CCL25 on MOLT4 cell invasion, migration and metastasis. The effects of Wnt5a on MOLT4 cell actin polarization and pseudopodium formation were examined using laser scanning confocal microscopy and scanning electron microscopy. CCL25 induced Wnt5a expression in MOLT4 cells by promoting protein kinase C (PKC) expression and activation. Wnt5a promoted MOLT4 cell migration, invasion, actin polarization, and lamellipodium and filopodia formation via PI3K/Akt-RhoA pathway activation. These effects were rescued by PI3K/Akt or RhoA knockdown or inhibition. Additionally, Wnt5a in cooperation with CCL25 promoted MOLT4 cell mouse liver metastasis and stimulated RhoA activation. These results show that CCL25/CCR9 upregulates Wnt5a by promoting PKC expression and activation in MOLT4 cells. This in turn promotes cell migration and invasion via PI3K/Akt-RhoA signaling, enhancing cell polarization and pseudopodium formation. These findings indicate that the PI3K/Akt-RhoA pathway is likely responsible for Wnt5a-induced adult T-ALL cell migration and invasion.

The role of chemokine receptor 9/chemokine ligand 25 signaling: From immune cells to cancer cells (Review)

“…In this study, glycogen synthase kinase 3 β (GSK-3β) and forkhead in human rhabdomyosarcoma (FKHR) were demonstrated to be downstream targets of Akt ( 73 ), which further influenced the migration, invasion and drug resistance of cancer cells. An alternative stimulation of PI3/Akt by wingless-type protein 5a (Wnt5a) following CCR9/CCL25 interaction was revealed in another study ( 74 ), indicating a complex cross-talk between these signaling pathways ( Fig. 2 ).…”

“…Mediation of cell invasion and migration by CCR9/CCL25 signaling may involve matrix metalloproteinases (MMPs) ( 55 , 56 , 60 ), Ras homologue (RhoA)Rho kinase (ROCK)-myosin light chain (MLC) signal ( 39 ), Wnt5a ( 74 ) and ERM protein family ( 38 ). In the ovarian cancer OVCAR-3 and CAOV-3 cell lines, CCR9/CCL25 selectively regulated certain MMPs, which degraded the cell matrix to promote invasion ( 55 ).…”

CCR9 and CCL25: A review of their roles in tumor promotion

“…Notably, knocking out AKT or inhibiting RhoA leads to the exact opposite direction of the results of Wnt5a activation. In addition, Wnt5a could synergize with CCL25 to enhance RhoA activation and promote MOLT4 cell migration and invasion (Deng et al, 2017).…”

Revisiting β‐Catenin Signaling in T‐Cell Development and T‐Cell Acute Lymphoblastic Leukemia

“…However, the non‐canonical and canonical pathways are quite intertwined and not simply dissociated . In T‐ALL, the expression of “non‐canonical” ligand Wnt5a by leukemic cells affects the microenvironment by increasing osteoclastogenesis, and promoting T‐ALL migration …”