Mitochondrial metabolism as a potential novel therapeutic target for lung adenocarcinoma

Abstract

Background Lung adenocarcinoma (LUAD) is the most common histological type of lung cancer and one of the leading causes of cancer-related deaths worldwide. The prognosis for LUAD patients remains unsatisfactory. To improve the prognosis of LUAD patients, identifying novel therapeutic targets is necessary. Oxidative phosphorylation (OXPHOS) is involved in the progression and metastasis of several cancers. This study evaluated the role of OXPHOS in LUAD and determined the potential for LUAD cell growth suppression by inhibiting OXPHOS metabolism. Methods Gene expression profiles, clinicopathological characteristics, and prognosis of lung cancer patients were evaluated using the OXPHOS or glycolysis-related RNA-seq data extracted from The Cancer Genome Atlas (TCGA) dataset. PPARγ expression, a representative OXPHOS molecule, was investigated using TCGA dataset and immunohistochemistry of surgically resected LUAD specimens. Expression of glycolysis-related molecules HIF1a, and LDH and OXPHOS-related molecules UCP2 and PPARγ and the effects of OXPHOS inhibitors oligomycin and metformin on cell growth were examined in human LUAD cell lines. Results High expression of OXPHOS-related genes was associated with worse prognosis and lymph node metastasis than that observed with low expression of OXPHOS-related genes (p = 0.07 and p < 0.01, respectively). In LUAD patients (n = 500), high PPARγ expression (n = 109) was associated with significantly worse prognosis than that seen with low PPARγ expression (n = 391) (5-year OS, high 34% vs. low 42%) (p = 0.01). PPARγ, detected in the invasive component of LUAD, was expressed only in the peripheral area. A549, HTB181, and H322 cells were classified as OXPHOS-high type, and H596 cells were classified as OXPHOS-low type, based on OXPHOS and glycolysis-related gene expression. Oligomycin treatment inhibited the proliferation of these OXPHOS-high-type cell lines (ratio of oligomycin 1.0 µM to control; A549:0.72, HTB181:0.69, H322:0.77, p < 0.01, respectively) but not of the OXPHOS-low expression type cell lines. Conclusions LUADs can be classified as high and low OXPHOS types, with heterogeneity in individual tumors. Inhibition of OXPHOS metabolism may represent a novel therapeutic strategy for LUAD patients with a high expression of OXPHOS-related genes.