Reversal of Warburg Effect and Reactivation of Oxidative Phosphorylation by Differential Inhibition of EGFR Signaling Pathways in Non–Small Cell Lung Cancer

Abstract

Purpose: One of the hallmarks of cancer cells is the excessive conversion of glucose to lactate under normoxic conditions, also known as the Warburg effect. Here, we tested whether the targeted inhibition of EGFR may revert this effect and reactivate mitochondrial oxidative phosphorylation in non-small cell lung cancer (NSCLC).Experimental Design: Sensitive (HCC827) and resistant (H1975 and H1993) NSCLC cells were treated with a panel of EGFR or MET inhibitors, and then tested for changes of EGFR signaling, glycolytic cascade, and mitochondrial function. Silencing of key glycolytic enzymes was then performed with targeted siRNAs. Furthermore, tumor-bearing nude mice treated with EGFR inhibitors were evaluated with 18 F-FDG PET/CT and tumors were analyzed for glycolytic and mitochondrial proteins.Results: Effective inhibition of EGFR signaling in NSCLC cells induced a dramatic reduction of hexokinase II (HKII) and phospho-pyruvate kinase M2 (p-PKM2, Tyr105) levels as well as an upregulation of mitochondrial complexes subunits (OXPHOS). Accordingly, a decreased lactate secretion and increased intracellular ATP levels were also observed in response to EGFR inhibitors. Downregulation of HKII and PKM2 by targeted siRNA transfection did not cause upregulation of OXPHOS but enhanced the effects of EGFR TKIs. Conversely, selective inhibition of AKT and ERK1/2 caused OXPHOS upregulation and glycolysis inhibition, respectively. Similar findings were obtained in tumors from animals treated with appropriate EGFR inhibitors.Conclusions: Our findings indicate that EGFR inhibitors may reactivate oxidative phosphorylation of cancer cells and provide a mechanistic clue for the rational combination of agents targeting EGFR-dependent proliferation and glucose metabolism in cancer therapy.

The Effect of Diabetes Mellitus on Lung Cancer Prognosis

“…34 Further research by De Rosa et al indicate that EGF pathways are associated with cancer metabolism and inhibition of EGF pathways may have the synergistic antitumor effect with the therapeutic strategies targeting glucose metabolism through reversal of Warburg effect and reactivation of oxidative phosphorylation in NSCLC. 35 However, except for the cancer-promoting effects of DM, there may be some other feasible effects of DM on the poor survival in lung cancer patients. For example, patients with DM generally present with more advanced stages of lung cancer, which may contribute to the inferior OS of lung cancer patients with DM.…”

2-Deoxy-d-glucose Suppresses the In Vivo Antitumor Efficacy of Erlotinib in Head and Neck Squamous Cell Carcinoma Cells

“…Increased EGFR signaling promotes glucose metabolism through various mechanisms including increased Akt-dependent glycolysis (9), stabilization of the SGLT1 glucose transporter (10,11), increased STAT3 signaling (via HIF1 and GLUT1 (12–15)), and increased pyruvate kinase M2 (PKM2) activity (16). EGFR inhibition was shown to down regulate glycolysis accompanied by suppression of key glycolytic enzymes including hexokinase-II (HKII) and pyruvate kinase M2 (PKM2) (17). Glycolysis inhibition has been shown to selectively induce cancer cell death while sparing normal untransformed cells by increasing mitochondrial oxidative stress (18).…”

Identifying reproducible cancer-associated highly expressed genes with important functional significances using multiple datasets

“…3a). Besides, the DNA replication pathway19 commonly found by PD and SAM, the other 13 significant pathways are mainly associated with lung cancer, including pentose phosphate pathway20, oxidative phosphorylation921, cysteine and methionine metabolism22, glutathione metabolism101112, biosynthesis of amino acids23, ribosome24, proteasome13, protein processing in endoplasmic reticulum2526, phagosome27 and TNF signaling pathway28. These conservative pathways included many DE genes highly expressed in both cancer and normal tissues, which tended to be missed by SAM.…”

“…Because genes with low expression levels are more likely to reach large FCs than genes with high expression levels, SAM is also biased to genes with low expression levels8. Compared with genes expressed at low levels, genes expressed at high levels are more likely to be involved in some functionally conserved pathways such as oxidative phosphorylation9, glutathione metabolism101112 and proteasome13 with important biological significances.…”