Nina Kokkonen, Elham Khosrowabadi, Antti Hassinen, Deborah Harrus, Tuomo Glumoff, Thomas Kietzmann, and Sakari Kellokumpu. Antioxidants & Redox Signaling. Jan 2019.ahead of print. http://doi.org/10.1089/ars.2017.7389
Abnormal golgi pH homeostasis in cancer cells impairs apical targeting of carcinoembryonic antigen by inhibiting its glycosyl-phosphatidylinositol anchor-mediated association with lipid rafts
|Author:||Kokkonen, Nina1; Khosrowabadi, Elham1; Hassinen, Antti1;|
1Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland
|Online Access:||PDF Full Text (PDF, 1.8 MB)|
|Persistent link:|| http://urn.fi/urn:nbn:fi-fe2019071022983
Mary Ann Liebert,
|Publish Date:|| 2019-07-10
Aims: Carcinoembryonic antigen (CEACAM5, CEA) is a known tumor marker for colorectal cancer that localizes in a polarized manner to the apical surface in normal colon epithelial cells whereas in cancer cells it is present at both the apical and basolateral surfaces of the cells. Since the Golgi apparatus sorts and transports most proteins to these cell surface domains, we set out here to investigate whether any of the factors commonly associated with tumorigenesis, including hypoxia, generation of reactive oxygen species (ROS), altered redox homeostasis, or an altered Golgi pH, are responsible for mistargeting of CEA to the basolateral surface in cancer cells.
Results: Using polarized nontumorigenic Madin-Darby canine kidney (MDCK) cells and CaCo-2 colorectal cancer cells as targets, we show that apical delivery of CEA is not affected by hypoxia, ROS, nor changes in the Golgi redox state. Instead, we find that an elevated Golgi pH induces basolateral targeting of CEA and increases its TX-100 solubility, indicating impaired association of CEA with lipid rafts. Moreover, disruption of lipid rafts by methyl-β-cyclodextrin induced accumulation of the CEA protein at the basolateral surface in MDCK cells. Experiments with the glycosylphosphatidylinositol (GPI)-anchorless CEA mutant and CEA-specific GPI-anchored enhanced green fluorescent protein (EGFP-GPI) fusion protein revealed that the GPI-anchor was critical for the pH-dependent apical delivery of the CEA in MDCK cells.
Innovation and Conclusions: The findings indicate that an abnormal Golgi pH homeostasis in cancer cells is an important factor that causes mistargeting of CEA to the basolateral surface of cancer cells via inhibiting its GPI-anchor-mediated association with lipid rafts.
Antioxidants & redox signaling
|Pages:||5 - 21|
|Type of Publication:||
A1 Journal article – refereed
|Field of Science:||
1182 Biochemistry, cell and molecular biology
This study was supported by grants from the Finnish Glycoscience Graduate School, The Emil Aaltonen Foundation, The Maud Kuistila Memorial Foundation, The Finnish Cultural Foundation, and The Academy of Finland.
© 2018, Mary Ann Liebert, Inc., publishers. This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/).