Targeting OXPHOS and the electron transport chain in cancer; Molecular and therapeutic implications

Greene, John; Segaran, Ashvina; Lord, Simon

doi:10.1016/j.semcancer.2022.02.002

Cited by 78 publications

(47 citation statements)

References 128 publications

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“…Using these cell lines, we evaluated the role of OXPHOS metabolism on LUAD cell proliferation using OXPHOS inhibitors. The OXPHOS pathway generates ATP by transferring electrons to a series of transmembrane protein complexes in the inner mitochondrial membrane, a process known as the electron transport chain (ETC) (20). As electrons pass through the multiprotein ETC complexes I-IV, protons are pumped from the mitochondrial matrix to the intermembrane space by complexes I, III, and IV.…”

Section: Discussionmentioning

confidence: 99%

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Mitochondrial metabolism as a potential novel therapeutic target for lung adenocarcinoma

Fujiwara

Mimae

Kushitani

et al. 2023

Preprint

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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.

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Section: Discussionmentioning

confidence: 99%

“…For pursuing this novel treatment strategy concept, characterizing the metabolic activity of OXPHOS in heterogeneous LUAD is essential. Furthermore, several recent trials have highlighted mitochondrial metabolism as a target for antitumor therapy (see Additional File 1) [20,21]. However, its antitumor effects on LUAD remain unclear.…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial metabolism as a potential novel therapeutic target for lung adenocarcinoma

Fujiwara

Mimae

Kushitani

et al. 2023

Preprint

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“…Tsvetko et al have proposed that cuproptosis was associated with high mitochondrial reactivity oxidative phosphorylation (OXPHOS) (Tsvetkov et al, 2022). Despite an increasing reliance on glycolysis, it is becoming evident that many cancer cells still have functional OXPHOS (Greene et al, 2022). A report by Aminzadeh-Gohari et al demonstrated that OXPHOS was markedly increased in melanoma cells (Aminzadeh-Gohari et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

A novel risk model based on cuproptosis-related lncRNAs predicted prognosis and indicated immune microenvironment landscape of patients with cutaneous melanoma

Zhou

Shen

et al. 2022

Front. Genet.

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Cutaneous melanoma (CM) is an aggressive form of malignancy with poor prognostic value. Cuproptosis is a novel type of cell death regulatory mechanism in tumors. However, the role of cuproptosis-related long noncoding RNAs (lncRNAs) in CM remains elusive. The cuproptosis-related lncRNAs were identified using the Pearson correlation algorithm. Through the univariate and multivariate Cox regression analysis, the prognosis of seven lncRNAs associated with cuproptosis was established and a new risk model was constructed. ESTIMATE, CIBERSORT, and single sample gene set enrichment analyses (ssGSEA) were applied to evaluate the immune microenvironment landscape. The Kaplan–Meier survival analysis revealed that the overall survival (OS) of CM patients in the high-risk group was remarkably lower than that of the low-risk group. The result of the validated cohort and the training cohort indicated that the risk model could produce an accurate prediction of the prognosis of CM. The nomogram result demonstrated that the risk score based on the seven prognostic cuproptosis-related lncRNAs was an independent prognostic indicator feature that distinguished it from other clinical features. The result of the immune microenvironment landscape indicated that the low-risk group showed better immunity than high-risk group. The immunophenoscore (IPS) and immune checkpoints results conveyed a better benefit potential for immunotherapy clinical application in the low-risk groups. The enrichment analysis and the gene set variation analysis (GSVA) were adopted to reveal the role of cuproptosis-related lncRNAs mediated by the immune-related signaling pathways in the development of CM. Altogether, the construction of the risk model based on cuproptosis-related lncRNAs can accurately predict the prognosis of CM and indicate the immune microenvironment of CM, providing a new perspective for the future clinical treatment of CM.

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“…The most numerous are small molecules inhibiting mitochondrial CI, such as the biguanides Metformin and Phenformin, fenofibrate, and IACS-010759 [8,10]. Some of these CI inhibitors induce cancer cell death through a mechanism that involves increased ROS production or interaction with AMP-activated protein kinase (AMPK) and hypoxia inducible factor 1-alpha (HIF1-α) signaling [8].…”

Section: Textmentioning

confidence: 99%

A novel anticancer pharmacological agent targeting mitochondrial complex I

Reyes-Castellanos

Carrier

2022

Trends in Pharmacological Sciences

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Targeting OXPHOS and the electron transport chain in cancer; Molecular and therapeutic implications

Cited by 78 publications

References 128 publications

Mitochondrial metabolism as a potential novel therapeutic target for lung adenocarcinoma

Mitochondrial metabolism as a potential novel therapeutic target for lung adenocarcinoma

A novel risk model based on cuproptosis-related lncRNAs predicted prognosis and indicated immune microenvironment landscape of patients with cutaneous melanoma

A novel anticancer pharmacological agent targeting mitochondrial complex I

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