Potassium and Sodium Channels and the Warburg Effect: Biophysical Regulation of Cancer Metabolism

Abstract

Ion channels are progressively emerging as a novel class of membrane proteins expressed in several types of human cancers and regulating the different aspects of cancer cell behavior. The metabolism of cancer cells, usually composed by a variable proportion of respiration, glycolysis, and glutaminolysis, leads to the excessive production of acidic metabolic products. The presence of these acidic metabolites inside the cells results in intracellular acidosis, and hinders survival and proliferation. For this reason, tumor cells activate mechanisms of pH control that produce a constitutive increase in intracellular pH (pH i) that is more acidic than the extracellular pH (pH e). This condition forms a perfect microenvironment for metastatic progression and may be permissive for some of the acquired characteristics of tumors. Recent analyses have revealed complex interconnections between oncogenic activation, ion channels, hypoxia signaling and metabolic pathways that are dysregulated in cancer. Here, we summarize the molecular mechanisms of the Warburg effect and hypoxia and their association. Moreover, we discuss the recent findings concerning the involvement of ion channels in various aspects of the Warburg effect and hypoxia, focusing on the role of Na + and K + channels in hypoxic and metabolic reprogramming in cancer.

Divergent expression of hypoxia response systems under deoxygenation in reef‐forming corals aligns with bleaching susceptibility

“…Expression of genes encoding for K2P K + ion channels (TASK‐like) was consistent over time for both species, irrespective of experimental condition (Figure 3biii). Only A. tenuis showed a peak in expression after 0.5 hr of deoxygenation (T1), thus indicating a greater HIF‐induced sensitivity in response to short‐term deoxygenation (Iorio et al., 2019; Shin et al., 2014). Genes encoding for the glycolytic enzymes lactate dehydrogenase B ( LDH ) and pyruvate dehydrogenase kinase 4 ( PDK ) that are key to promoting anaerobic respiration exhibited dynamic expression changes over time.…”

Toward Hijacking Bioelectricity in Cancer to Develop New Bioelectronic Medicine

“…An example of this is the tPMET Duodenal cytochrome B (DcytB) which interacts with ascorbic acid and iron ions in which the cation ion is transported by divalent metal transporter 1 (DMT1) cation transporters. Many of the above will also lead to pH changes that will cause further alterations in ion channel activity and V m , [89] but may also lead to the creation of an acidic tumor microenvironment. Acidification of the tumor microenvironment has been shown to affect invasion, metastasis, and resistance to therapeutics [89][90][91] (Figure 4:8).…”

“…[27] For instance, non-metastatic colorectal adenocarcinoma patients presented a correlation between expression of hERG1 and GLUT-1, where hERG1 positive and GLUT-1 negative expression represents an independent negative prognostic factor. [89] Dichloroacetate (DCA) presents a dual effect by reversing and downregulating Kv1.5 channels, increasing membrane polarization, and by inducing a shift in metabolism from cytoplasmbased glycolysis to a mitochondria-based glucose oxidation. [210] This combined mechanism can decrease tumor growth and induce a pro-apoptotic effect.…”

“…Many of the above will also lead to pH changes that will cause further alterations in ion channel activity and V m , [ 89 ] but may also lead to the creation of an acidic tumor microenvironment. Acidification of the tumor microenvironment has been shown to affect invasion, metastasis, and resistance to therapeutics [ 89–91 ] (Figure 4:8).…”

“…[ 27 ] For instance, non‐metastatic colorectal adenocarcinoma patients presented a correlation between expression of hERG1 and GLUT‐1, where hERG1 positive and GLUT‐1 negative expression represents an independent negative prognostic factor. [ 89 ]…”