Abnormal Golgi pH Homeostasis in Cancers: Its Causes and Consequences on Cancer Cell Malignant Phenotype

Correct glycosylation, i.e., attachment of sugars to cellular proteins and lipids, is essential for all multicellular life, from fertilization to embryonic growth and development, and the maintenance and proper functioning of tissues and organs throughout the life cycle of the individual. This ability is primarily based on the presence of a sugar coat, glycocalyx, around all cells in our body, as it helps to connect cells to each other and the extracellular connective tissue or matrix. It also provides protection against invading pathogens and sometimes hostile environment around the cells. The Golgi complex is an acidic organelle in the cell and primarily responsible for manufacturing and linking sugar chains to cellular proteins and lipids in a defined order via characteristic linkage type of each sugar. In many diseases, such as cancers, the ability of the Golgi complex to make structurally normal sugar chains is lost. The resulting abnormal sugar chains are important as they contribute to the survival, growth, motility, and ability of cancer cells to penetrate and form metastases in surrounding tissues. The causes of these alterations remain thus far incompletely understood.

In this thesis, the aim was to study the causes and consequences of an altered Golgi pH homeostasis in cancer cells and its significance in the conversion of cancer cells to malignant state. We showed that the pH of Golgi lumen is unusually high (almost neutral) in all cancer cell lines studied. In approximately half of the cell lines, this increase was caused by the increased number of bicarbonate chloride exchangers (AE2, SLC4A2) in the Golgi, and thus, increased import of bicarbonate anions, which then neutralizes the Golgi lumen. In addition, the exceptionally high Golgi pH of cancer cells was found to contribute to their ability to penetrate tissues by altering both the structure of the sugar chains and by interfering with the maintenance of special cell surface domains present in normal epithelial cells. Both changes are typical in cancer cells. The study also identified several hormone and cell attachment receptors that carry abnormal sugar structures using a snail lectin (Helix Pomatia agglutinin) as a probe. These modified cell surface receptors likely are responsible for the malignancy and spread of cancer cells to surrounding tissues. These findings may to be useful in cancer treatments in the future.