Low-pH-induced apoptosis: role of endoplasmic reticulum stress-induced calcium permeability and mitochondria-dependent signaling

Abstract

The acidic microenvironment around tumor cells is a major determinant in cancer growth, metabolism, and metastasis. However, its role in cancer physiology is still not clearly understood. In the present investigation, an attempt has been made to explore the effect of acidic environment on physiology of cancer cells. Exposure of Raji cells to extracellular acidic environment was associated with enhanced cytosolic calcium level and endoplasmic reticulum stress response. X-box binding protein 1 (XBP1) splicing, CCAAT/ enhancer-binding protein homologous protein (CHOP), and glucose-regulated protein 78 kDa (GRP78) upregulation suggested endoplasmic reticulum stress generation. On the other hand, real-time-based upregulation of Bax gene expression and flow cytometric analysis of cytochrome c release as well as enhanced active caspase-3 further confirmed mitochondrion-mediated events leading to induction of apoptosis. The expression of TP53 and p21 was upregulated. These observations collectively strongly suggest that both endoplasmic reticulum stress-mediated calcium release and Bax targeting might be altering mitochondrion membrane potential which in turn could induce secondary apoptotic signals; subsequently, endoplasmic reticulum stress can also lead to nuclear localization of Nuclear factor-κB (NF-κB) which in turn favors p53 mediated apoptotic signals.

Extracellular acidification induces ROS- and mPTP-mediated death in HEK293 cells

“…Changes in the cellular (micro)environment profoundly affect cell physiology and are associated with induction of pathology [64] , [9] . A key property of the extracellular environment is its pH (pHe), which has to be maintained within strict boundaries to allow proper cellular function and prevent cell death [43] , [51] . Alterations in cellular energy metabolism often induce extracellular acidification, the rate and mechanism of which depend on the cell type and used energy substrate [37] .…”

The Roles of Acidosis in Osteoclast Biology

“…Typically, extracellular acidosis promotes inflammatory cell defense against pathogens by regulating migration and phagocytosis (Martinez et al, 2006 ). However, lactic acidosis caused by increase in glycolysis during tumorigenesis facilitates tumor invasion and metastasis, and has deleterious effects on biological processes (Rofstad et al, 2006 ; Sharma et al, 2015 ). Recent results from in vivo studies have shown that bone loss related to acidosis was not due to passive physicochemical dissolution of bone minerals but rather increased osteoclastic resorption (Kraut et al, 1984 ; Meghji et al, 2001 ).…”

Simultaneous determination of malondialdehyde and 3‐nitrotyrosine in cultured human hepatoma cells by liquid chromatography–mass spectrometry

“…This could be explained by the strongly inhibited function of mitochondrial electron transport chain, the main intracellular source of ROS, in dying cells (Moore et al, ; Ott, Gogvadze, Orrenius, & Zhivotovsky, ). Another explanation of lower MDA levels observed after 4 and 24 h may lie in increased MDA degradation and/or higher reactivity of MDA toward other biomolecules (e.g DNA) accelerated by low pH in dying cells, forming intra‐ and intermolecular crosslinks (Ayala, Muñoz, & Argüelles, ; Sharma, Kaur, Bhatnagar, & Kaur, ). Also, excessive accumulation of intracellular disulfides (e.g.…”