Monoamine Oxidase A Inhibits Lung Adenocarcinoma Cell Proliferation by Abrogating Aerobic Glycolysis

Abstract

Lung adenocarcinoma (LUAD) accounts for ~30% of all lung cancers and is one of the causes of cancer-related death worldwide. As the role of monoamine oxidase A (MAOA) in LUAD remains unclear, in this study, we examine how MAOA affects LUAD cell proliferation. Analyses of both public data and our data reveal that the expression of MAOA is downregulated in LUAD compared with non-tumor tissue. In addition, the expression of MAOA in tumors correlates with clinicopathologic features, and the expression of MAOA serves as an independent biomarker in LUAD. In addition, the overexpression of MAOA inhibits LUAD cell proliferation by inducing G1 arrest in vitro. Further mechanistic studies show that MAOA abrogates aerobic glycolysis in LUAD cells by decreasing hexokinase 2 (HK2). Finally, the expression of HK2 shows a negative correlation with MAOA in LUAD, and high HK2 predicts poor clinical outcome. In conclusion, our findings indicate that MAOA functions as a tumor suppressor in LUAD. Our results indicate that the MAOA/HK2 axis could be potential targets in LUAD therapy.

Keywords: aerobic glycolysis; cell prolferation; hexokinase 2; lung adenocarcinoma; monoamine oxidase A.

Figure 1

The expression of monoamine oxidase A (MAOA) in lung adenocarcinoma (LUAD). The expression of MAOA in gene expression omnibus (GEO) data (A), 19 pairs of human LUAD specimens (B), 15 pairs of mice induced LUAD, 108 human LUAD specimens (C), and the gene expression profiling interactive analysis (GEPIA) database (D). The immunohistochemistry (IHC) detection of MAOA in human LUAD specimens (E). *p < 0.05, **p < 0.01, and ***p < 0.001, compared with non-tumor tissues.

Figure 2

The expression of MAOA correlates with the survival of patients with LUAD. (A) Survival of the patients in two groups according to the median of MAOA mRNA level in GEPIA. (B) The survival of the high MAOA group and low MAOA group analyzed by the Kaplan–Meier analysis.

Figure 3

Overexpressed MAOA affects LUAD cancer cell proliferation and growth in vitro. Colony formation (A) and MTT (B) assays performed to evaluate the effects of MAOA on LUAD cells (NCI-H1975 and A549). Flow cytometry (C) and Western blot (D) performed to analyze LUAD cell cycle and the G1/S cell cycle-related protein proliferating cell nuclear antigen (PCNA), respectively. Data are presented as mean + SD (n = 3). *p < 0.05, **p < 0.01 and ***p < 0.001, compared to the control group.

Figure 4

Aerobic glycolysis in MAOA-overexpressing LUAD cells. (A) Extracellular acidification rate [ECAR, (B) glucose consumption, and (C) lactate production were analyzed in MAOA-overexpressing and control LUAD cells. (D) The enzymatic activity and protein level of hexokinase 2 (HK2)] were detected by hexokinase activity assay and Western blot, respectively. Data are presented as mean + SD (n = 3). *p < 0.05, **p < 0.01, and ***p < 0.001, compared to the control group.

Figure 5

HK2 correlates negatively with MAOA in LUAD. The correlation between HK2 and MAOA was analyzed in the GEO dataset (A), GEPIA (B), and our collected LUAD tumors (C). The survival rate of patients with LUAD was analyzed in GEPIA according to the expression of HK2 (D).