Proceedings of The Physiological Society

Europhysiology 2018 (London, UK) (2018) Proc Physiol Soc 41, C030

Oral Communications

Regulation of constitutive cation entry and cell proliferation by TRPM7 channels in human pancreatic stellate cells.

T. Lefebvre1, A. Vanlaeys1, S. Radoslavova1, H. Ouadid-Ahidouch1, I. Dhennin-Duthille1, M. Gautier1

1. UFR Sciences, University of Picardie Jules Verne, Amiens, France.


Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancer with a 5-year survival rate less than 5%. This extremely poor prognosis is mainly due to a late diagnosis, to the occurrence of metastases, and to the absence of efficient treatment. Thus, there is an urgent need to better understand the cellular and molecular mechanisms that drive PDAC progression. Among them, it is now largely admitted that cancer cells interact with their close microenvironment when they invade the stroma. This reaction called "desmoplastic reaction" leads to the activation of pancreatic stromal cells and to the enhancement of cancer cell capacities to form metastasis in the neighboring organs. Indeed, the activated stromal cells or pancreatic stellate cells (PSCs) are studied as potential therapeutic targets in PDAC. Ion channels are involved in cancer cell proliferation, survival, migration, invasion, etc. Recently, we showed that TRPM7 channel expression is increased in human PDAC tissues compared to healthy tissues, and that TRPM7 expression is inversely related to patient survival. Moreover, TRPM7 regulates PDAC cell migration and invasion through constitutive Mg2+ entry (Rybarczyk et al., 2012; Rybarczyk et al., 2017). In the present work, we aim to assess the role of TRPM7 channels in human PSCs. We found that TRPM7 was expressed as both mRNA and protein level in human PSCs cell lines. By using Western-Blot and immunofluorescence staining, we also found an expression of the activation markers of PSCs including α-SMA, COX-2 and desmin. The inhibition of TRPM7 by siRNA or by a pharmacological blocker NS8593 (10 µM) induced the growth arrest of PSCs. Cell cycle analysis after TRPM7 inhibition showed an accumulation of PSCs in G0/G1 phase along with a decrease of the cell number in S and G2/M phases of the cell cycle. The number of apoptotic PSCs was also significantly increased by TRPM7 silencing. Finally, Mn2+ quench experiments showed the involvement of TRPM7 in cation constitutive entry in PSCs. In conclusion, we show that TRPM7 is required for PSCs proliferation and survival possibly by maintaining a constitutive cation entry. Further experiments are needed to determine how TRPM7 regulates PSCs growth (Ca2+ and/or Mg2+-dependent mechanisms?).

Where applicable, experiments conform with Society ethical requirements