Abstract 3039: Decreased pH-sensitive potassium channel gene expressions in glioblastomas compared to oligodendrogliomas detected with house keeping genes may shift glioblastoma membrane potentials towards proton efflux to the microenvironment

Abstract

Abstract Glial buffering of K+ prevents seizures, hence gliomas in patients on anticonvulsants may harbor potassium related anomalies. Cell membrane potentials are very sensitive to K+ and may link to tumor acidosis when they become more positive than the equilibrium potential for H+ ions (Vaupel, P, et al., Cancer Res, 1989). Kir5.1(KCNJ16) heterodimerizes with Kir4.1(KCNJ10), a major glial potassium channel, to stop K+ conductance in acidosis. Trek1&2(KCNK2&10) are also pH sensitive K+ channels. Glioblastomas (more malignant and invasive) versus oligodendrogliomas showed decreased KCNJ16 in patients on anticonvulsants (Beckner, ME, Proc AACR, A2319, 2021). However, loss of genomic integrity in tumors and potential variation between assays prompted house keeping gene (HKG) normalization to lessen confounding factors. REMBRANDT (12/31/2020, Georgetown Database of Cancer) had 220 glioblastomas and 67 oligodendrogliomas with microarray gene expression via medians of each reporter (1-8 per gene) in Adobe Flash readouts (ended 1/1/21). A subgroup, 75 glioblastomas and 24 oligodendroglioma patients, took anticonvulsants. Comparison of genes of interest (GOI) initially had t tests between types of gliomas in the subgroup. Here, differences between glioma types for each GOI reporter were compared to differences for HKGs (PPIA, RPLP0, YWHAZ, and B2M). In gliomas with anticonvulsants, paired 2-tailed t tests for a null difference of median reporters between tumor types were less sensitive than new comparisons of oligodendroglioma minus glioblastoma (OMG) differences for GOIs versus OMG differences in HKGs. For KCNJ16, the t test, p = 0.015, for a decrease in glioblastomas (versus oligodendrogliomas) in initial studies improved to p ≤ 0.0001 by using HKGs in comparisons. The KCNK2&10 decrease in glioblastomas became significant, p = 0.047. Among other glycolytic and acidosis related genes, CA12, GLO1&2, PFKFB1&3, showed stronger trends, with p values from 0.08 to 0.13 (decreases and increase) in comparisons using HKGs. Conclusion: HKG normalization presumably corrects for loss of genomic integrity, assay variations, etc. in comparisons using microarrays of different tumors. The pH-sensitive K+ channel genes studied here were expressed less in glioblastomas. The resulting pH-insensitive K+ distributions in glioblastomas putatively shift their cell membrane potentials to less negative values which are sufficient to allow passive H+ efflux that causes extracellular acidosis with accompanying activation of invasion. Acknowledgement: The data utilized in this study were provided by the Georgetown Database of Cancer (G-DOC), a project of the Georgetown Lombardi Comprehensive Cancer Center designed to provide translational research tools to the scientific community. Citation Format: Marie E. Beckner. Decreased pH-sensitive potassium channel gene expressions in glioblastomas compared to oligodendrogliomas detected with house keeping genes may shift glioblastoma membrane potentials towards proton efflux to the microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3039.