Aberrant environment and PS-binding to calnuc C-terminal tail drives exosomal packaging and its metastatic ability.

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.

• Authors: Ravichandran Vignesh, Anita Sjölander, Ganesh Venkatraman, Suresh Kumar Rayala, Gopala Krishna Aradhyam
• Journal: The Biochemical journal (Biochem J) Vol. 478 Issue 12 Pg. 2265-2283 (06 25 2021) ISSN: 1470-8728 [Electronic] England
• PMID: 34047336 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.

Chemical References

• Nucleobindins
• Phosphatidylserines

Topics

• Animals
• Carcinoma, Squamous Cell (metabolism, secondary)
• Cell Movement
• Cell Proliferation
• Epithelial-Mesenchymal Transition
• Exosomes (metabolism)
• Female
• Humans
• Mice
• Mice, Inbred C57BL
• Mouth Neoplasms (metabolism, pathology)
• Nucleobindins (genetics, metabolism)
• Pancreatic Neoplasms (metabolism, pathology)
• Phosphatidylserines (metabolism)
• Tumor Cells, Cultured
• Tumor Microenvironment