The Golgi as a “Proton Sink” in Cancer

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.

Structural insights into ion conduction by novel cation channel, TMEM87A, in Golgi apparatus

“…To execute these functions, maintaining ion and pH homeostasis of the Golgi lumen is critical [8][9][10] . Hence, dysregulation of Golgi ion and pH homeostasis can alter protein trafficking and glycosylation and even lead to Golgi disorganization, a cellular phenotype associated with various diseases such as cancer and neurodegenerative disease [11][12][13][14] . While several anion channels in the Golgi membrane, including Golgi pH regulator (GPHR), mid-1-related chloride channel (MClC), and voltage-gated chloride channels (ClC-3B) are known to counterbalance for Golgi acidification, much less is known about cation efflux channels in the Golgi.…”

Melatonin: Regulation of Prion Protein Phase Separation in Cancer Multidrug Resistance

“…Tumor hypoxia causes the metabolic shift towards acidity where proton (H + ) accumulation is proportional to O 2 levels [ 454 ]. Excess intracellular protons are often extruded into extracellular space via different mechanisms [ 455 ] including membrane transporters [ 456 ], carbonic anhydrase enzymes [ 457 ], and lysosomes [ 458 ], or sequestered in proton sinks [ 459 ]. The ensuing acidic pH e may directly interfere with the efficacy of weakly basic chemotherapeutic drugs by impeding their intracellular distribution through “ion trapping” [ 460 ].…”

Intracellular pH links energy metabolism to lymphocyte death and proliferation

“…The acidic tumor microenvironment promotes tumorigenesis by facilitating tumor cell invasion of local tissues (Corbet and Feron, 2017; Estrella et al, 2013). Overactive acid extrusion and sequestration in organelles such as the Golgi apparatus lead to higher intracellular pH (pHi) in tumor cells than untransformed cells (Galenkamp and Commisso, 2021; Stock and Pedersen, 2017). The elevated pH is required for the optimal activities of a number of enzymes in the glycolytic and pentose phosphate pathways, which appears to form a positive feedback loop between the Warburg effect and high pHi to promote tumorigenesis (Alfarouk et al, 2020; Galenkamp and Commisso, 2021).…”

“…Overactive acid extrusion and sequestration in organelles such as the Golgi apparatus lead to higher intracellular pH (pHi) in tumor cells than untransformed cells (Galenkamp and Commisso, 2021; Stock and Pedersen, 2017). The elevated pH is required for the optimal activities of a number of enzymes in the glycolytic and pentose phosphate pathways, which appears to form a positive feedback loop between the Warburg effect and high pHi to promote tumorigenesis (Alfarouk et al, 2020; Galenkamp and Commisso, 2021). However, the contribution of the other aspect of the Warburg effect the reduction or loss of mitochondrial respiration to the high pHi in the tumor cells is unknown.…”