Cell Settling, Migration, and Stochastic Cancer Expression Suggest Potassium Flux Per H+- Sensitive KCN Members Associated with Oncogenes and Histone/DNA Modulators Potentially Initiates pH-Reversal

Abstract

Attraction of glioblastoma cells to potassium was suspected when cells clustered around dying cells and they migrated towards serum (high [K+]) and a positive potassium gradient. Potassium channel proteins (KCN family, 90 members) mediating altered transmembrane flux may provide K+ that releases H+ bound to inner membranes in cancer cells for cytosolic proton transfer (possibly Grotthuss) to extrusion sites. Cell settling and migration assay results led to collection of 70 studies, unbiased by authors for inclusion of KCN genes, that detected KCN differentially expressed genes (DEG). Of 53 KCN DEG found among 29 malignancies, 62.3% encoded H+-sensitive proteins. KCN DEG encoding H+-sensitive proteins were more prevalent in 50 studies involving one or more of 8 categories (7 oncogenes and histone/DNA modifiers) versus those with none, p = 0.0325. Pertinent genes for lactate outflow, etc. had relatively normal expressions. Brain tumors in REMBRANDT (database) showed altered expression of KCN genes encoding H+-sensitive proteins in glioblastomas versus less invasive oligodendrogliomas of patients on anti-seizure medications, with less KCNJ16 /Kir5.1, p = 5.32 x 10-8. Altered H+-sensitive potassium flux via the KCN family downstream of oncogenes and histone/DNA modifiers putatively incites proton transfers for H+ release during pH reversal in cancer. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=103 SRC="FIGDIR/small/662144v2_ufig1.gif" ALT="Figure 1"> View larger version (50K): org.highwire.dtl.DTLVardef@565c1forg.highwire.dtl.DTLVardef@1ba0df6org.highwire.dtl.DTLVardef@1eabf7forg.highwire.dtl.DTLVardef@c24eb5_HPS_FORMAT_FIGEXP M_FIG Graphical Abstract Steps in K+/H+ Dynamics for pH Reversal in Cells. Step1. Potassium ions accumulate near cell membranes if (A) inward flow channels bring in more K+ than normal or (B) if the diffuse low outward flow channels are nonfunctional with compensation by channels in a few locations that are high flow requiring contributions of solvated potassium (K+-7H2O) from deeper cell regions. Step2. K+ reaches the inner cell membrane where H+ is bound diffusely to its negative charges. Step3. As K+-7H2O desolvates (for channel exit or membrane binding), the release of 7H2O may augment or form Grotthuss water wires near inner membrane surfaces. Step4. At the inner membrane K+ exchanges with H+. As H+ is released, it becomes H3O+ and diffuses into the cytosol. Step5. H3O+ enters a Grotthuss water wire that enables rapid proton transfer (conformational) to H+ exit sites. Step6. H+ leaves the cell with lactate or it exits via other H+ extruders. The cytosolic pH increases and the external pH decreases for pH reversal. C_FIG