A small-molecule ligand of valosin-containing protein/p97 inhibits cancer cell–accelerated fibroblast migration

Abstract

Edited by George N. DeMartino Carcinoma-associated fibroblasts are fibroblasts activated by surrounding cancer cells. Carcinoma-associated fibroblasts exhibit enhanced cell migration, which plays an important role in cancer metastasis. Previously, we demonstrated enhanced migration of NIH3T3 fibroblasts when they were cultured in the presence of MCF7 breast cancer cells. Human fibroblasts displayed a similar phenomenon even when they were co-cultured with cancer cells other than MCF7 cells. In this study, we screened ϳ16,000 compounds from the RIKEN Natural Products Depository chemical library for inhibitors of enhanced NIH3T3 cell migration in the presence of MCF7. We identified NPD8733 as an inhibitor of cancer cell-enhanced fibroblast migration. This inhibition was observed not only in a woundhealing co-culture assay but also in a Transwell migration assay. Using NPD8733 and a structurally similar but inactive derivative, NPD8126, on immobilized beads, we found that NPD8733, but not NPD8126, specifically binds to valosin-containing protein (VCP)/p97, a member of the ATPase-associated with diverse cellular activities (AAA؉) protein family. Using VCP truncation variants, we found that NPD8733 binds to the D1 domain of VCP. Because VCP's D1 domain is important for its function, we concluded that NPD8733 may act on VCP by binding to this domain. siRNA-mediated silencing of VCP in NIH3T3 fibroblasts, but not in MCF7 cells, reduced the migration of the co-cultured NIH3T3 fibroblasts. These results indicate that MCF7 activates the migration of NIH3T3 cells through VCP and that NPD8733 binds VCP and thereby inhibits its activity.

PPARα Inhibition Overcomes Tumor-Derived Exosomal Lipid-Induced Dendritic Cell Dysfunction

“…In addition to cancer cells, other cells in the TME may produce exosomes and affect DC function. To rule out this possibility, in vitro we collected the exosomes from NIH 3T3 cells, a non-cancerous cell line with a fibroblast phenotype ( Suvarna et al, 2019 ). We treated BMDCs with equal amounts of exosomes derived from tumor cells or NIH 3T3 cells and measured their change in intracellular lipids and T cell priming capability.…”

Extracellular Matrix: Emerging Roles and Potential Therapeutic Targets for Breast Cancer

“…They found that a smallmolecule ligand (NPD8733) of valosin-containing protein/p97 inhibited cancer cell-accelerated fibroblast migration. This mechanism offers potential for BC treatment (97). Many activated CAFs are present in the BC stroma, and they have the ability to promote tumor formation and development.…”

A novel function of AAA-ATPase p97/VCP in the regulation of cell motility

“…As such, ROCK proteins are less active leading to dynamic actin network formation and ultimately, increased cell migration potential. A recent study also reported that a chemical inhibitor of p97/VCP also inhibited mouse fibroblast cell migration [35].…”