O-GlcNAcylation homeostasis controlled by calcium influx channels regulates multiple myeloma dissemination
Abstract Background Multiple myeloma (MM) cell motility is a critical step during MM dissemination throughout the body, but how it is regulated remains largely unknown. As hypercalcemia is an important clinical feature of MM, high calcium (Ca2+) and altered Ca2+ signaling could be a key contributing...
Main Authors: | , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
BMC
2021-03-01
|
Series: | Journal of Experimental & Clinical Cancer Research |
Subjects: | |
Online Access: | https://doi.org/10.1186/s13046-021-01876-z |
id |
doaj-6b4f196d14904b42bb71550efc6d4ae7 |
---|---|
record_format |
Article |
spelling |
doaj-6b4f196d14904b42bb71550efc6d4ae72021-03-21T12:06:19ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662021-03-0140111710.1186/s13046-021-01876-zO-GlcNAcylation homeostasis controlled by calcium influx channels regulates multiple myeloma disseminationParinya Samart0Sudjit Luanpitpong1Yon Rojanasakul2Surapol Issaragrisil3Graduate Program in Immunology, Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol UniversitySiriraj Center of Excellence for Stem Cell Research, Faculty of Medicine Siriraj Hospital, Mahidol UniversityWVU Cancer Institute and Department of Pharmaceutical Sciences, West Virginia UniversitySiriraj Center of Excellence for Stem Cell Research, Faculty of Medicine Siriraj Hospital, Mahidol UniversityAbstract Background Multiple myeloma (MM) cell motility is a critical step during MM dissemination throughout the body, but how it is regulated remains largely unknown. As hypercalcemia is an important clinical feature of MM, high calcium (Ca2+) and altered Ca2+ signaling could be a key contributing factor to the pathological process. Methods Bioinformatics analyses were employed to assess the clinical significance of Ca2+ influx channels in clinical specimens of smoldering and symptomatic MM. Functional and regulatory roles of influx channels and downstream signaling in MM cell migration and invasion were conducted and experimental MM dissemination was examined in a xenograft mouse model using in vivo live imaging and engraftment analysis. Results Inhibition of TRPM7, ORAI1, and STIM1 influx channels, which are highly expressed in MM patients, and subsequent blockage of Ca2+ influx by CRISPR/Cas9 and small molecule inhibitors, effectively inhibit MM cell migration and invasion, and attenuate the experimental MM dissemination. Mechanistic studies reveal a nutrient sensor O-GlcNAcylation as a downstream regulator of Ca2+ influx that specifically targets cell adhesion molecules. Hyper-O-GlcNAcylation following the inhibition of Ca2+ influx channels induces integrin α4 and integrin β7 downregulation via ubiquitin-proteasomal degradation and represses the aggressive MM phenotype. Conclusions Our findings unveil a novel regulatory mechanism of MM cell motility via Ca2+ influx/O-GlcNAcylation axis that directly targets integrin α4 and integrin β7, providing mechanistic insights into the pathogenesis and progression of MM and demonstrating potential predictive biomarkers and therapeutic targets for advanced MM.https://doi.org/10.1186/s13046-021-01876-zO-GlcNAcylationCalcium influxMultiple myelomaTRPM7ORAI1STIM1 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Parinya Samart Sudjit Luanpitpong Yon Rojanasakul Surapol Issaragrisil |
spellingShingle |
Parinya Samart Sudjit Luanpitpong Yon Rojanasakul Surapol Issaragrisil O-GlcNAcylation homeostasis controlled by calcium influx channels regulates multiple myeloma dissemination Journal of Experimental & Clinical Cancer Research O-GlcNAcylation Calcium influx Multiple myeloma TRPM7 ORAI1 STIM1 |
author_facet |
Parinya Samart Sudjit Luanpitpong Yon Rojanasakul Surapol Issaragrisil |
author_sort |
Parinya Samart |
title |
O-GlcNAcylation homeostasis controlled by calcium influx channels regulates multiple myeloma dissemination |
title_short |
O-GlcNAcylation homeostasis controlled by calcium influx channels regulates multiple myeloma dissemination |
title_full |
O-GlcNAcylation homeostasis controlled by calcium influx channels regulates multiple myeloma dissemination |
title_fullStr |
O-GlcNAcylation homeostasis controlled by calcium influx channels regulates multiple myeloma dissemination |
title_full_unstemmed |
O-GlcNAcylation homeostasis controlled by calcium influx channels regulates multiple myeloma dissemination |
title_sort |
o-glcnacylation homeostasis controlled by calcium influx channels regulates multiple myeloma dissemination |
publisher |
BMC |
series |
Journal of Experimental & Clinical Cancer Research |
issn |
1756-9966 |
publishDate |
2021-03-01 |
description |
Abstract Background Multiple myeloma (MM) cell motility is a critical step during MM dissemination throughout the body, but how it is regulated remains largely unknown. As hypercalcemia is an important clinical feature of MM, high calcium (Ca2+) and altered Ca2+ signaling could be a key contributing factor to the pathological process. Methods Bioinformatics analyses were employed to assess the clinical significance of Ca2+ influx channels in clinical specimens of smoldering and symptomatic MM. Functional and regulatory roles of influx channels and downstream signaling in MM cell migration and invasion were conducted and experimental MM dissemination was examined in a xenograft mouse model using in vivo live imaging and engraftment analysis. Results Inhibition of TRPM7, ORAI1, and STIM1 influx channels, which are highly expressed in MM patients, and subsequent blockage of Ca2+ influx by CRISPR/Cas9 and small molecule inhibitors, effectively inhibit MM cell migration and invasion, and attenuate the experimental MM dissemination. Mechanistic studies reveal a nutrient sensor O-GlcNAcylation as a downstream regulator of Ca2+ influx that specifically targets cell adhesion molecules. Hyper-O-GlcNAcylation following the inhibition of Ca2+ influx channels induces integrin α4 and integrin β7 downregulation via ubiquitin-proteasomal degradation and represses the aggressive MM phenotype. Conclusions Our findings unveil a novel regulatory mechanism of MM cell motility via Ca2+ influx/O-GlcNAcylation axis that directly targets integrin α4 and integrin β7, providing mechanistic insights into the pathogenesis and progression of MM and demonstrating potential predictive biomarkers and therapeutic targets for advanced MM. |
topic |
O-GlcNAcylation Calcium influx Multiple myeloma TRPM7 ORAI1 STIM1 |
url |
https://doi.org/10.1186/s13046-021-01876-z |
work_keys_str_mv |
AT parinyasamart oglcnacylationhomeostasiscontrolledbycalciuminfluxchannelsregulatesmultiplemyelomadissemination AT sudjitluanpitpong oglcnacylationhomeostasiscontrolledbycalciuminfluxchannelsregulatesmultiplemyelomadissemination AT yonrojanasakul oglcnacylationhomeostasiscontrolledbycalciuminfluxchannelsregulatesmultiplemyelomadissemination AT surapolissaragrisil oglcnacylationhomeostasiscontrolledbycalciuminfluxchannelsregulatesmultiplemyelomadissemination |
_version_ |
1724210898723143680 |