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. 2021 Feb;10(2):817-826.
doi: 10.21037/tcr-20-2598.

The effects of hypoxia on mitochondrial function and metabolism in gastric cancer cells

Jun Jiang  1 , Yuan Jiang  2 , Yao-Gang Zhang  2 , Tao Zhang  3 , Jian-Hua Li  2 , Deng-Liang Huang  2 , Jing Hou  2 , Mei-Yuan Tian  2 , Li Sun  2 , Xiao-Ming Su  3 , Yun Dong  3 , Yan-Yan Ma  2   4
Affiliations

The effects of hypoxia on mitochondrial function and metabolism in gastric cancer cells

Jun Jiang et al. Transl Cancer Res. 2021 Feb.

Abstract

Background: A number of studies have found that metabolic disorders are the characteristic manifestations of tumor cells. However, the effects of hypoxic environment on mitochondrial function and glucose metabolism of tumor cells were still unclear. The study wanted to explore the regulatory mechanism of hypoxic environment on mitochondrial function and metabolism in gastric cancer cells.

Methods: The animal model of gastric cancer and MKN45 were treated in a hypoxic environment. Mitochondrial membrane potential and reactive oxygen species (ROS) levels were analyzed by flow cytometry, qPCR was used to detect the expression levels of glycose metabolism key enzymes, damage repair genes and mitochondrial DNA (mtDNA) copy numbers in gastric cancer.

Results: Compared with 2,000 m normal gastric cancer tissue, the decreased of mitochondrial membrane potential and the production of ROS reduced, the expressions of glucose metabolism genes [the M1 isoform of Hexokinase (HK1), pyruvate kinase (PKM), Succinate dehydrogenase (SDHA), Glucose-6-phosphate dehydrogenase (G6PD)], homologous recombination repair gene (RAD51) and repair DNA double-stranded broken gene (ASTCT2) increased, and aerobic respiration reduced in gastric cancer cells. In the hypoxic environment, the decreased of mitochondrial membrane potential reduced, the production of ROS and mtDNA copies increased, HK1 expression increased, the expressions of SDHA, G6PD, RAD51 and ASCT-2 decreased, and the aerobic respiration decreased.

Conclusions: Hypoxia plays an important role in maintaining mitochondrial functions in gastric cancer cells by promoting glycolysis and inhibiting mitochondrial aerobic respiration capacity.

Keywords: Gastric cancer; aerobic respiration; hypoxia; mitochondrial function.

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Conflict of interest statement

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/tcr-20-2598). The authors have no conflicts of interest to declare.

Figures

Figure 1
Figure 1
Results of gastric tissue mitochondrial membrane potential and ROS. (A) Normal and model mice gastric. (B) The results of mitochondrial membrane potential. (C) The results of mitochondrial membrane potential. (D) The results of ROS. (E) The results of ROS. Four samples per time point and 3 sample tubes per sample for flow cytometry. P3 represents a decrease in mitochondrial membrane potential. P2 represents the generation of ROS.
Figure 2
Figure 2
Results of gastric tissue mtDNA. The recombinant plasmid of cytochrome B (Cyt-B) gene sequence encoded by mtDNA of rats was constructed as a standard, and the Cyt-B gene in mitochondria of rat stomach tissues was quantified by real-time quantitative PCR, so as to achieve the absolute quantitative determination of mtDNA content. (A) The standard curve. (B) The sample amplification curve. (C) Standard product amplification curve. (D) The result of gastric tissue mtDNA.
Figure 3
Figure 3
The level of HK1, PKM, SDHA, G6PDCT-2, RAD51 and ASCT-2 mRNA in gastric tissue. (A) The level of HK1 mRNA. (B) The level of PKM mRNA. (C) The level of SDHA mRNA. (D) The level of G6PD mRNA; (E) The level of AST2 mRNA. (F) The level of mRNA.
Figure 4
Figure 4
Results of hypoxia mitochondrial membrane potential and ROS in MKN45. (A,B) The results of MKN45 mitochondrial membrane potential. (C,D) Present the results of MKN45 ROS. (E) The statistical of MKN45 mitochondrial membrane potential. (F) The statistical of MKN45 ROS.
Figure 5
Figure 5
Results of MKN45 mtDNA.
Figure 6
Figure 6
Results of HK1, PKM, SDHA, G6PDCT-2, RAD51 and ASCT-2 mRNA in MKN45. (A) The level of HK1 mRNA. (B) The level of SDHA mRNA. (C) The level of G6PD mRNA. (D) The level of AST2 mRNA. (E) The level of RAD5 mRNA. (F) The level of PKM mRNA.
Figure 7
Figure 7
The seahorse analysis of the MKN45. (A) Mitochondrial stress test steps. (B) the O2 consumption rate (OCR) of MKN45 at different oxygen concentrations. (C) The proton leak. (D) ATP production. (E) Spare respiratory capacity. Pairwise comparison using independent sample t-test.
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