TRPM7/RPSA Complex Regulates Pancreatic Cancer Cell Migration

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a malignancy with a very poor prognosis due to highly metastatic profile. Cell migration is an essential step of the metastatic cascade allowing cancer cells to spread toward target tissues. Recent studies strongly suggest that bioactive elastin peptides, also named elastokines or elastin-derived peptides (EDPs), are released in the extracellular microenvironment during tumoral remodeling of the stroma. EDPs stimulate cancer cell migration by interacting with their membrane receptor, ribosomal protein SA (RPSA). Others membrane proteins like ion channels are also involved in cancer cell migration. It has been recently shown that the transient receptor potential melastatin-related 7 (TRPM7) channel regulates PDAC cell migration and invasion. The objective of this work was to study the effect of EDPs on TRPM7 channel in human pancreatic cancer cells. We showed that EDPs promote MIA PaCa-2 cell migration using Boyden chamber assay. Cells transfected with a siRNA targeting TRPM7 were not able to migrate in response to EDPs indicating that TRPM7 regulated cell migration induced by these peptides. Moreover, EDPs were able to stimulate TRPM7 currents recorded by Patch-Clamp. Finally, we showed that TRPM7 channels and RPSA receptors are colocalized at the plasma membrane of human pancreatic cancer cells. Taken together, our data suggest that TRPM7/RPSA complex regulated human pancreatic cancer cell migration. This complex may be a promising therapeutic target in PDAC.

Critical role of lipid membranes in polarization and migration of cells: a biophysical view

“…Proteolytic cleavage of the integrinactin binding does not reduce the cell adhesion but also promote the cell migration . In fact, the upregulation of Fam38 and TRPM7 substantially facilitates the migration and invasion of cancer cells (Lefebvre et al 2020;McHugh et al 2012). In the second mechanism, the key force generator disrupting the weak adhesion contacts is stress fibers (Yumura and Fukui 1985).…”

AG-9, an Elastin-Derived Peptide, Increases In Vitro Oral Tongue Carcinoma Cell Invasion, through an Increase in MMP-2 Secretion and MT1-MMP Expression, in a RPSA-Dependent Manner

“…In vivo study showed that AG-9 peptide promotes melanoma progression even more than the well described VG-6 peptide. These results were confirmed by in vitro studies in proliferation assays, migration assays, adhesion assays, proteinase secretion studies, and pseudotube formation assays to investigate angiogenesis [18,34].…”

“…Elastin was reported to interact with invasive cancer cells through RPSA [ 33 ]. Previous experiments from our laboratory identified RPSA as AG-9 receptor on HT-1080 human fibrosarcoma cell surface [ 19 ], and on MIA PaCa-2 cell pancreatic adenocarcinoma cells [ 34 ]. We first checked for RPSA expression in CAL 27 cells, compared to MIA PaCa-2 cells.…”

“…Additionally, 50 mM kappa-elastin increases CAL 27 invasion through transwell previously coated with Matrigel ® which mimicks basement membrane. AG-9 also significantly increased CAL 27 invasion, as previously reported for MIA PaCa-2 pancreatic ductal adenocarcinoma cells [ 34 ]. EDP were previously reported to increase MMP secretion, especially MMP-2 [ 44 , 45 ].…”

Mg2+ Transporters in Digestive Cancers

“…Finally, TRPM7 channels are also involved in the interaction between PDAC cells and the tumoral microenvironment because TRPM7 membrane currents and TRPM7-dependent cell migration are both stimulated following treatment with elastin-derived peptides (EDP) that are released by the degradation of the extracellular matrix. Our study suggests that TRPM7 is involved in the response to EDP through its interaction with the ribosomal protein SA (RPSA) [ 93 ].…”