A novel TRPM7/O-GlcNAc axis mediates tumour cell motility and metastasis by stabilising c-Myc and caveolin-1 in lung carcinoma

Sudjit Luanpitpong,Siwaporn Klamkhlai,Napachai Rodboon,Surapol Issaragrisil,Chanida Vinayanuwattikun,Pithi Chanvorachote,Parinya Samart,Yon Rojanasakul

doi:10.1038/s41416-020-0991-7

Abstract

BackgroundCalcium is an essential signal transduction element that has been associated with aggressive behaviours in several cancers. Cell motility is a prerequisite for metastasis, the major cause of lung cancer death, yet its association with calcium signalling and underlying regulatory axis remains an unexplored area.MethodsBioinformatics database analyses were employed to assess correlations between calcium influx channels and clinical outcomes in non-small cell lung cancer (NSCLC). Functional and regulatory roles of influx channels in cell migration and invasion were conducted and experimental lung metastasis was examined using in vivo live imaging.ResultsHigh expression of TRPM7 channel correlates well with the low survival rate of patients and high metastatic potential. Inhibition of TRPM7 suppresses cell motility in various NSCLC cell lines and patient-derived primary cells and attenuates experimental lung metastases. Mechanistically, TRPM7 acts upstream of O-GlcNAcylation, a post-translational modification and a crucial sensor for metabolic changes. We reveal for the first time that caveolin-1 and c-Myc are favourable molecular targets of TRPM7/O-GlcNAc that regulates NSCLC motility. O-GlcNAcylation of caveolin-1 and c-Myc promotes protein stability by interfering with their ubiquitination and proteasomal degradation.ConclusionsTRPM7/O-GlcNAc axis represents a potential novel target for lung cancer therapy that may overcome metastasis.

Highlights

Calcium is an essential signal transduction element that has been associated with aggressive behaviours in several cancers
We first performed survival analysis in human non-small cell lung cancer (NSCLC) patients using Kaplan–Meier plotter based on messenger RNA (mRNA) expression of TRPM7, ORAI1 and STIM1 to assess the clinical significance of these major channels
CRISPR/Cas[9] system was used to inhibit TRPM7 and Orai[1] in NSCLC National Cancer Institute (NCI)-H292 cells and cell invasion, which is a critical step in the metastatic process, was determined by the transwell assay

Summary

Introduction

Calcium is an essential signal transduction element that has been associated with aggressive behaviours in several cancers. Lung cancer is the leading cause of cancer death that kills more than one million people worldwide each year, due largely to diagnosis at late stages with local or distant organ metastasis.[7] Cancer cell migration and invasion into surrounding tissues through basement membranes are an initial step in metastasis, allowing the dissemination of primary tumour cells into blood circulation to establish new or secondary tumour sites.[8,9] Recent studies have emphasised that Ca2+ channels that are associated with aggressive cancer behaviours are primarily non-voltageactivated channels and belong to transient receptor potential (TRP) superfamily and Orai family.[10,11,12] The TRP proteins that are frequently modified during cancer progression include TRP canonical (TRPC1 and 6), TRP vanilloid (TRPV2 and 6) and TRP melastatin (TRPM7 and 8).

Methods

Results

Conclusion