SLC4A2 anion exchanger promotes tumour cell malignancy via enhancing net acid efflux across golgi membranes

Abstract

Proper functioning of each secretory and endocytic compartment relies on its unique pH micro-environment that is known to be dictated by the rates of V-ATPase-mediated H+ pumping and its leakage back to the cytoplasm via an elusive “H+ leak” pathway. Here, we show that this proton leak across Golgi membranes is mediated by the AE2a (SLC4A2a)-mediated bicarbonate-chloride exchange, as it is strictly dependent on bicarbonate import (in exchange for chloride export) and the expression level of the Golgi-localized AE2a anion exchanger. In the acidic Golgi lumen, imported bicarbonate anions and protons then facilitate a common buffering reaction that yields carbon dioxide and water before their egress back to the cytoplasm via diffusion or water channels. The flattened morphology of the Golgi cisternae helps this process, as their high surface-volume ratio is optimal for water and gas exchange. Interestingly, this net acid efflux pathway is often upregulated in cancers and established cancer cell lines, and responsible for their markedly elevated Golgi resting pH and attenuated glycosylation potential. Accordingly, AE2 knockdown in SW-48 colorectal cancer cells was able to restore these two phenomena, and at the same time, reverse their invasive and anchorage-independent growth phenotype. These findings suggest a possibility to return malignant cells to a benign state by restoring Golgi resting pH.

Prognostic 7-SLC-Gene Signature Identified via Weighted Gene Co-Expression Network Analysis for Patients with Hepatocellular Carcinoma

“…Furthermore, ROC analysis was performed to validate the sensitivity and specifcity of the prognostic signature.SLC2A2 encodes glucose transporter protein 2 (GLUT2), which is associated with glycolysis and gluconeogenesis in the liver via the HNF4a-GLUT2 pathway that can afect the uptake and utilization of glucose by HCC cells and is involved in the systemic metabolism of cancer cachexia [36,37]. Te SLC4A2 gene encodes bicarbonate-chloride anion exchange protein 2 (AE2), which mediates proton leakage across the Golgi membrane and allows the Golgi apparatus to act as a proton reservoir in cancer cells, thereby regulating the pH microenvironment of TCS and promoting tumourigenesis and progression [38]. Malfunction of the acid-base homeostasis caused by SLC4A2 can also afect mitochondrial gradients and trigger ROS damage, leading to apoptosis, proliferation, and morphological alterations [39].…”

The integrated on-chip isolation and detection of circulating tumour cells

“…54 Firstly, an electrostatic enrichment was achieved by modifying a channel with a polymer/lipid layer. As cancer cells are known to have an increased expression of anion transporters on their surface, 143,144 CTCs flowing through the channel were observed to have a temporary but increased electrostatic interaction with the positively charged lipid layer than healthy cells. 54 The second design aspect capitalised on the larger size and dielectrophoretic properties of these CTCs.…”

Role of voltage-gated proton channel (Hv1) in cancer biology

“…iv) Cl − /HCO 3 − anion-exchanger (AE). AEs are chloride-bicarbonate transporters, where AE2a overexpression is associated with an incremented cell malignancy in colorectal cancer cells ( Khosrowabadi et al, 2021 ), and v) Vacuolar (H + )-ATPases. V-ATPase is a proton pump that promotes the transport of protons in disfavor of their chemical gradient, coupled to ATP consumption.…”