ZACN Associated with Poor Prognosis Promotes Proliferation of Kidney Renal Clear Cell Carcinoma Cells by Inhibiting JTC801-Induced Alkaliptosis

Abstract

Alkaliptosis, crucial in various cancers, is a specific form of cell death. This study aims to screen a prognosis-related gene in kidney renal clear cell carcinoma (KIRC) using the alkaliptosis gene set and to investigate the roles of the gene in KIRC and its association with alkaliptosis. Transcriptome and clinical information of KIRC patients were collected from the TCGA-KIRC and GSE29609 database. We detected ZACN levels in normal kidney cells and KIRC cells and assessed the ZACN and JTC801-induced alkaliptosis relationship using immunoblotting and pH measurement. In the alkaliptosis gene set (IKBKB, NFKB1, CA9, CHUK, IKBKG, and RELA), NFKB1, CHUK, and IKBKG exhibited differential expression in TCGA-KIRC. Based on these three genes, two alkaliptosis patterns were identified in TCGA-KIRC. The independent prognostic gene for KIRC, ZACN, was screened. High ZACN in KIRC patients indicated a poor prognosis. ZACN was inversely related to the infiltration of anti-cancer immune cells such as CD4 + T cells, macrophages, and neutrophils, and it regulated the immune checkpoint and gene mutations. Patients characterized by high ZACN levels exhibited a heightened drug sensitivity to ABT737_1910, 5-Fluorouracil_1073, etc. ZACN expression in KIRC cells was increased relative to normal kidney cells and was inhibited in a concentration-dependent manner by JTC801. ZACN overexpression suppressed p-p65/p65 expression, increased expression of CA9, and lowered intracellular pH. In KIRC, ZACN inhibits JTC801-induced alkaliptosis. This study sheds light on a novel mechanism involving ZACN and alkaliptosis in KIRC, offering a promising avenue for further research and potential therapeutic interventions in KIRC management.