Reversal of Cancer Cell Invasiveness Via Reprogramming Their Golgi pH Homeostasis

Abstract

Cancer invasiveness and metastatic spread are the main causes of cancer-associated deaths, yet successful therapies for their prevention are currently non-existing. Here we exploit cancer cell reprogramming, a strategy developed earlier to prevent tumour growth, to show that cancer cell invasiveness can be reversed via restoring their Golgi pH homeostasis and normal glycosylation status. Specifically, we demonstrate that AE2a (SLC4A2a)-mediated bicarbonate-chloride exchange controls proton leakage across Golgi membranes via a well-known buffering reaction that produces water and carbon dioxide from luminal protons and bicarbonate anions. Its forced overexpression in non-malignant cells, or upregulation in certain cancer cells in vitro and in vivo, also coincides with elevated Golgi resting pH, the synthesis of invasion and metastasis-promoting glycans and a shorter life span of cancer patients. Finally, AE2 knockdown in cancer cells blocked their invasiveness via restoring their Golgi pH homeostasis and normal glycosylation status. Thus, cancer metastasis is a reversible process that can be targeted by addressing organelle pH homeostasis.