Emerging links between endosomal pH and cancer

Abstract

Extracellular acidification is a well-known driver of tumorigenesis that has been extensively studied. In contrast, the role of endosomal pH is novel and relatively unexplored. There is emerging evidence from a growing number of studies showing that the pH of endosomal compartments controls proliferation, migration, stemness, and sensitivity to chemoradiation therapy in a variety of tumors. Endosomes are a crucial hub, mediating cellular communication with the external environment. By finely regulating the sorting and trafficking of vesicular cargo for degradation or recycling, endosomal pH determines the fate of plasma membrane proteins, lipids, and extracellular signals including growth factor receptors and their ligands. Several critical regulators of endosomal pH have been identified, including multiple isoforms of the family of electroneutral Na⁺/H⁺ exchangers (NHE) such as NHE6 and NHE9. Recent studies have shed light on molecular mechanisms linking endosomal pH to cancer malignancy. Manipulating endosomal pH by epigenetic reprogramming, small molecules, or nanoparticles may offer promising new options in cancer therapy. In this review, we summarize evidence linking endosomal pH to cancer, with a focus on the role of endosomal Na⁺/H⁺ exchangers and how they affect the prognosis of cancer patients, and also suggest how regulation of endosomal pH may be exploited to develop new cancer therapies.

Keywords: And protons; Breast cancer; Chemoresistance; Glioblastoma; NHE6; NHE9; RACK1; Sodium-hydrogen exchanger.

Figure 1.. Endosomal pH is determined by a balance of proton pump and leak mechanisms.

The concerted action of the V-type H⁺-ATPase and members of the CLC family of H⁺/Cl⁻ exchangers acidifies the lumen of endosomes. Intracellular members of the NHE family of Na⁺/H⁺ exchangers finely tune endosomal pH by leaking protons in exchange for Na⁺ and K⁺.

Figure 2.. Molecular mechanisms proposed for NHE isoforms in cancer.

A. In response to hypoxia, RACK1 mediates the translocation of NHE6 from the endosomes of breast cancer cells to the plasma membrane. This results in acidification of endosomal compartment and sequestration of weakly basic drugs such as doxorubicin. B. Upon treatment of cancer cells with chemotherapy and radiation, RACK1 is released from the C-terminal tail of NHE9 to facilitate downstream activation of Src/Akt/β-Catenin and Bcl-2 pathway, resulting in chemoradiation resistance. C. In glioblastoma, NHE9 is highly expressed, resulting in alkalinization of the endosomal lumen. As a result, oncogenic receptors such as EGFR escape degradation and are recycled back to the plasma membrane to drive tumor growth, migration and chemoresistance. D. NHE5 level is elevated in rat C5 glioblastoma cell line, where it acidifies the endosomal compartment. High levels of NHE5 are proposed to increase EGFR, MET, and integrinβ on the cell surface to drive proliferation and migration of cancer cells.

Figure 3.. Gene alterations in endosomal NHE across cancer subtypes.

Alterations are shown for NHE9 (top) and NHE6 (bottom) and comprise mutation, amplification, and deep deletion. Amplifications may include focal gene amplifications or larger chromosome parts such as whole chromosome gains. Combined RNA-Seq V2 and mutational data from 10,953 patients included in the TCGA PanCancer study across 32 tumor types. Dataset is from cBioPortal.

Figure 4.. Somatic mutations in endosomal NHE found in cancer.

Lollipop representation of the frequency and types of somatic mutations found in NHE9 gene (SLC9A9, top) and NHE6 gene (SLC9A6, bottom). Predicted PTM (post-translational modification) sites are also indicated. The data shows SLC9A9 gene harbors mutations on two phosphorylation sites (S355L and Y631*) and one N-linked glycosylation site (N96Y) in cancer.