Mitochondrial Metabolism as a Potential Novel Therapeutic Target for Lung Adenocarcinoma

Abstract

Background/aim: Oxidative phosphorylation (OXPHOS) is implicated in cancer progression and metastasis. However, its role in lung adenocarcinoma (LUAD) is unknown. We assessed OXPHOS in LUAD cases and cell lines and investigated the effect of OXPHOS inhibition on LUAD cells.

Materials and methods: The cases with high expression of OXPHOS-related genes and peroxisome proliferator-activated receptor gamma (PPAR-γ) were extracted using RNA-seq data from The Cancer Genome Atlas (TCGA) LUAD dataset and the clinicopathological features and survival were assessed. Resected LUAD specimens were stained for PPAR-γ. Real-time qPCR and western blot were used to examine the expression of OXPHOS- and glycolysis-related genes and proteins in four LUAD cell lines. Cell proliferation was evaluated in LUAD cells treated with OXPHOS inhibitors.

Results: The TCGA database analysis revealed that cases with high OXPHOS or PPAR-γ expression had a worse prognosis (p=0.07 and p=0.01, respectively). High OXPHOS cases were associated with lymph node metastasis (p<0.01). PPAR-γ was expressed only in the peripheral area of the papillary component of LUAD. We identified A549, HTB181 and H322 as OXPHOS-high type cells and H596 as OXPHOS-low type cells. Oligomycin treatment inhibited cell proliferation in the OXHOS-high cells (0.72-, 0.69-, and 0.77- fold change in oligomycin vs. DMSO, for A549, HTB181, and H322 cells, respectively, p<0.01) but not in the OXPHOS-low cells.

Conclusion: High expression of OXPHOS-related genes and PPAR-γ is a poor prognostic factor in LUAD. The levels of OXPHOS vary among cases and within different areas of the tumor. Targeting OXPHOS metabolism may represent a novel therapeutic approach for treating LUAD.

Keywords: Lung neoplasms; adenocarcinoma of lung; oxidative phosphorylation; therapeutics.