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.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) represents 85–90% of all pancreatic cancer types
These results showed that elastin-derived peptides (EDPs) increased PDAC cell migration without changing the cell viability
Our results show that EDPs increased PDAC cell migration in a transient receptor potential melastatin-related 7 (TRPM7) dependent manner
Summary
Pancreatic ductal adenocarcinoma (PDAC) represents 85–90% of all pancreatic cancer types. The incidence of PDAC is continuously increasing in such a way that PDAC is expected to be the second cancer in term of mortality in 2030 (Rahib et al, 2014). PDAC is characterized by an abundant desmoplastic stroma that participates to the formation of metastasis and chemoresistance. This remodeled stroma is a complex structure composed of extracellular matrix (ECM) proteins and various cell types. Cancer development is influenced by ECM components.
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