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Journal of Experimental & Clinical Cancer Research
Published in: Journal of Experimental & Clinical Cancer Research 1/2021

01-12-2021 | Acidosis | Research

Impact of the acidic environment on gene expression and functional parameters of tumors in vitro and in vivo

Authors: Mandy Rauschner, Luisa Lange, Thea Hüsing, Sarah Reime, Alexander Nolze, Marcel Maschek, Oliver Thews, Anne Riemann

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2021

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Abstract

Background

The low extracellular pH (pHe) of tumors resulting from glycolytic metabolism is a stress factor for the cells independent from concomitant hypoxia. The aim of the study was to analyze the impact of acidic pHe on gene expression on mRNA and protein level in two experimental tumor lines in vitro and in vivo and were compared to hypoxic conditions as well as combined acidosis+hypoxia.

Methods

Gene expression was analyzed in AT1 prostate and Walker-256 mammary carcinoma of the rat by Next Generation Sequencing (NGS), qPCR and Western blot. In addition, the impact of acidosis on tumor cell migration, adhesion, proliferation, cell death and mitochondrial activity was analyzed.

Results

NGS analyses revealed that 147 genes were uniformly regulated in both cell lines (in vitro) and 79 genes in both experimental tumors after 24 h at low pH. A subset of 25 genes was re-evaluated by qPCR and Western blot. Low pH consistently upregulated Aox1, Gls2, Gstp1, Ikbke, Per3, Pink1, Tlr5, Txnip, Ypel3 or downregulated Acat2, Brip1, Clspn, Dnajc25, Ercc6l, Mmd, Rif1, Zmpste24 whereas hypoxia alone led to a downregulation of most of the genes. Direct incubation at low pH reduced tumor cell adhesion whereas acidic pre-incubation increased the adhesive potential. In both tumor lines acidosis induced a G1-arrest (in vivo) of the cell cycle and a strong increase in necrotic cell death (but not in apoptosis). The mitochondrial O2 consumption increased gradually with decreasing pH.

Conclusions

These data show that acidic pHe in tumors plays an important role for gene expression independently from hypoxia. In parallel, acidosis modulates functional properties of tumors relevant for their malignant potential and which might be the result of pH-dependent gene expression.
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Metadata
Title
Impact of the acidic environment on gene expression and functional parameters of tumors in vitro and in vivo
Authors
Mandy Rauschner
Luisa Lange
Thea Hüsing
Sarah Reime
Alexander Nolze
Marcel Maschek
Oliver Thews
Anne Riemann
Publication date
01-12-2021
Publisher
BioMed Central
Keyword
Acidosis
Published in
Journal of Experimental & Clinical Cancer Research / Issue 1/2021
Electronic ISSN: 1756-9966
DOI
https://doi.org/10.1186/s13046-020-01815-4

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