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Emerging links between endosomal pH and cancer

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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.

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Abbreviations

EGFR:

Epidermal growth factor receptor

ESCC:

Esophageal squamous cell carcinoma

GBM:

Glioblastoma

GPCR:

G protein coupled receptor

GEF:

Guanine nucleotide exchange factor

NHE:

Sodium hydrogen exchanger

RTK:

Receptor tyrosine kinase

Tfn:

Transferrin

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Acknowledgments

M.J.K acknowledges the support of the graduate training programs in Cellular & Molecular Medicine and Nanotechnology for Cancer Research at the Johns Hopkins University.

Funding

M.J.K. is a recipient of Ruth L. Kirschstein Individual National Research Service Award F31CA220967. R.R. acknowledges the support of grants from the NIH (R01DK108304) and BSF (13044). A.Q.H. was supported by the Mayo Clinic Professorship, the Mayo Clinic Clinician Investigator award, the Florida Department of Health Cancer Research Chair Fund, as well as the National Institutes of Health (R43CA221490, R01CA200399, R01CA195503, R01CA216855).

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  1. Department of Physiology, The Johns Hopkins University School of Medicine, 725 N. Wolfe St, Baltimore, MD, 21205, USA

    Myungjun Ko & Rajini Rao

  2. Department of Neurological Surgery, Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, FL, 32224, USA

    Myungjun Ko & Alfredo Quiñones-Hinojosa

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M.J.K., R.R., and A.Q.H. wrote the paper and M.J.K. made the figures.

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Ko, M., Quiñones-Hinojosa, A. & Rao, R. Emerging links between endosomal pH and cancer. Cancer Metastasis Rev 39, 519–534 (2020). https://doi.org/10.1007/s10555-020-09870-1

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