Analysis of the metabolic proteome of lung adenocarcinomas by reverse-phase protein arrays (RPPA) emphasizes mitochondria as targets for therapy

Abstract

Lung cancer is the leading cause of cancer-related death worldwide despite the success of therapies targeting oncogenic drivers and immune-checkpoint inhibitors. Although metabolic enzymes offer additional targets for therapy, the precise metabolic proteome of lung adenocarcinomas is unknown, hampering its clinical translation. Herein, we used Reverse Phase Protein Arrays to quantify the changes in enzymes of glycolysis, oxidation of pyruvate, fatty acid metabolism, oxidative phosphorylation, antioxidant response and protein oxidative damage in 128 tumors and paired non-tumor adjacent tissue of lung adenocarcinomas to profile the proteome of metabolism. Steady-state levels of mitochondrial proteins of fatty acid oxidation, oxidative phosphorylation and of the antioxidant response are independent predictors of survival and/or of disease recurrence in lung adenocarcinoma patients. Next, we addressed the mechanisms by which the overexpression of ATPase Inhibitory Factor 1, the physiological inhibitor of oxidative phosphorylation, which is an independent predictor of disease recurrence, prevents metastatic disease. We highlight that IF1 overexpression promotes a more vulnerable and less invasive phenotype in lung adenocarcinoma cells. Finally, and as proof of concept, the therapeutic potential of targeting fatty acid assimilation or oxidation in combination with an inhibitor of oxidative phosphorylation was studied in mice bearing lung adenocarcinomas. The results revealed that this therapeutic approach significantly extended the lifespan and provided better welfare to mice than cisplatin treatments, supporting mitochondrial activities as targets of therapy in lung adenocarcinoma patients.

Multi-omics Research on the Heterogeneity and Immune Landscape of Lung Adenocarcinoma with Ground-glass opacity

“…Moreover, the GAPDH and GPD1 modi cations were consistent with prior research ndings, and enhanced glucose uptake is a functional biomarker with worse overall survival (OS) and disease-free survival (DFS). In contrast, increased tumor GPD1 levels were correlated with better OS and DFS [12] . This indicates mitochondria are more important in solid lung adenocarcinoma.…”

“…Pure-solid lung adenocarcinoma preferred to use glycolysis, an ine cient metabolic pathway for energy metabolism. However, AD-G had lower energy requirements than AD-S, resulting in lower glycolysis-associated gene expression [12] .…”

Betulinic acid counteracts the lipid accumulation in Caenorhabditis elegans by modulation of nhr-49 expression

“…Moreover, the leading neuroprotection effect was observed upon the hybrid combination between orlistat and grape seed extract [48]. Also, orlistat inhibits FASN and is investigated as an anti-neoplastic agent as an adjuvant to the conventional therapy of adenocarcinomas [49] as well as for its monotherapy [50]. Despite the synergistic combination with orlistat in the context of different biological activities described in the literature, in our experiment such cumulative effect was not observed upon combined treatment with orlistat (12 μM) and BA (50 μM) in C. elegans.…”

The Mitochondrial ATP Synthase/IF1 Axis in Cancer Progression: Targets for Therapeutic Intervention

“…Overall, we believe that the rewiring of energy metabolism represents a reversible adaptive phenotypic response of the cancer cell to the induction of proliferation, hypoxia and/or other agents of the tumor microenvironment, that results in the hyperstimulation of glycolysis and fermentation affecting mitochondrial OXPHOS in a cell-type specific manner. Energy metabolism provides a therapeutic target with great potential for the treatment of cancer patients, since it is a trait of the disease that is reversible and amenable to modifications by inhibitors of the enzymes that steer metabolism [20,[60][61][62][63][64][65][66].…”

“…The renascence of Warburg's postulates in the cancer field was spurred by the implementation of Positron Emission Tomography (PET) in clinical oncology, using the radionuclide 18 F-dexoxyglucose ( 18 FDG) [16][17][18], which represents the bed-side translation of Warburg's metabolic observation regarding the glucose avidity of tumors [19]. The cancer imaging technique stimulated metabolically oriented "omic" investigations of human carcinomas that opened up new windows of hope in cancer patients for its potential in diagnostic, staging, treatment and follow up of the disease [20][21][22][23][24][25]. In this review, we summarize the role of the mitochondrial ATP synthase and the role of its inhibitor protein, the ATPase Inhibitory Factor 1 (IF1), in metabolic rewiring of cancer and its progression to emphasize the relevance that the engine that controls cellular life and death has in this field of investigation.…”