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  1. Home
  2. Indian Institute of Technology Madras
  3. Publication2
  4. Aberrant environment and PS-binding to calnuc C-terminal tail drives exosomal packaging and its metastatic ability
 
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Aberrant environment and PS-binding to calnuc C-terminal tail drives exosomal packaging and its metastatic ability

Date Issued
01-06-2021
Author(s)
Vignesh, Ravichandran
Sjölander, Anita
Venkatraman, Ganesh
Suresh Rayala 
Indian Institute of Technology, Madras
A Gopala Krishna 
Indian Institute of Technology, Madras
DOI
10.1042/BCJ20210016
Abstract
The characteristic features of cancer cells are aberrant (acidic) intracellular pH and elevated levels of phosphatidylserine. The primary focus of cancer research is concentrated on the discovery of biomarkers directed towards early diagnosis and therapy. It has been observed that azoxymethane-treated mice demonstrate an increased expression of calnuc (a multi-domain, Ca2+- and DNA-binding protein) in their colon, suggesting it to be a good biomarker of carcinogenesis. We show that culture supernatants from tumor cells have significantly higher amounts of secreted calnuc compared to non-tumor cells, selectively packaged into exosomes. Exosomal calnuc is causal for epithelial-mesenchymal transition and atypical migration in non-tumor cells, which are key events in tumorigenesis and metastasis. In vitro studies reveal a significant affinity for calnuc towards phosphatidylserine, specifically to its C-terminal region, leading to the formation of 'molten globule' conformation. Similar structural changes are observed at acidic pH (pH 4), which demonstrates the role of the acidic microenvironment in causing the molten globule conformation and membrane interaction. On a precise note, we propose that the molten globule structure of calnuc caused by aberrant conditions in cancer cells to be the causative mechanism underlying its exosome-mediated secretion, thereby driving metastasis.
Volume
478
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