The Golgi as a "Proton Sink" in Cancer.

Koen M O Galenkamp,Cosimo Commisso

doi:10.3389/fcell.2021.664295

Abstract

Cancer cells exhibit increased glycolytic flux and adenosine triphosphate (ATP) hydrolysis. These processes increase the acidic burden on the cells through the production of lactate and protons. Nonetheless, cancer cells can maintain an alkaline intracellular pH (pHi) relative to untransformed cells, which sets the stage for optimal functioning of glycolytic enzymes, evasion of cell death, and increased proliferation and motility. Upregulation of plasma membrane transporters allows for H+ and lactate efflux; however, recent evidence suggests that the acidification of organelles can contribute to maintenance of an alkaline cytosol in cancer cells by siphoning off protons, thereby supporting tumor growth. The Golgi is such an acidic organelle, with resting pH ranging from 6.0 to 6.7. Here, we posit that the Golgi represents a “proton sink” in cancer and delineate the proton channels involved in Golgi acidification and the ion channels that influence this process. Furthermore, we discuss ion channel regulators that can affect Golgi pH and Golgi-dependent processes that may contribute to pHi homeostasis in cancer.

Highlights

Cancer cells require large amounts of energy in the form of adenosine triphosphate (ATP) to drive rapid proliferation and support cellular processes including the activation of cell signaling pathways, membrane transport, and DNA and protein synthesis (Alberts, 2015; Zhu and Thompson, 2019)
Cancer cells are generally equipped with a functional oxidative phosphorylation (OXPHOS) pathway, glucose metabolism is frequently switched to aerobic glycolysis where pyruvate is fermented to lactate, even when oxygen is available
A likely explanation is that organelle acidification plays a greater role in cancer cells due to the acidic burden that these cells have to withstand in response to amplified aerobic glycolysis and ATP hydrolysis (Webb et al, 2011; Corbet and Feron, 2017; Zheng et al, 2020)

Summary

INTRODUCTION

Cancer cells require large amounts of energy in the form of adenosine triphosphate (ATP) to drive rapid proliferation and support cellular processes including the activation of cell signaling pathways, membrane transport, and DNA and protein synthesis (Alberts, 2015; Zhu and Thompson, 2019). Increasing evidence shows that the regulation of pH homeostasis in cancer is not as straightforward as extrusion of protons at the plasma membrane level, as acidification of organelles, such as lysosomes and the Golgi, contributes to the maintenance of an alkaline cytosol (Liu et al, 2018; Funato et al, 2020; Galenkamp et al, 2020). These organelles function as repositories for H+ storage or means to extrude protons through an alternative pathway. This in contrast to previous studies where cAMP was found to alkalinize the Golgi, but where overexpression of CFTR did not significantly change the pH of the organelle (Seksek et al, 1995, 1996)

Findings

DISCUSSION

CONCLUSION