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Reversal of Warburg effect and reactivation of oxidative phosphorylation by differential inhibition of EGFR signaling pathways in non-small cell lung cancer.
No full textPURPOSE: 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
Phosphorylation of human pro-urokinase on Ser138/303 impairs its receptor-dependent ability to promote myelomonocytic adherence and motility
No full textCoordinate up-regulation of Sp1 DNA-binding activity and urokinase receptor expression in breast carcima
No full textCoordinate up-regulation of Sp1 DNA-binding activity and urokinase receptor expression in breast carcima
No full textUpregulation of epidermal growth factor receptor induced by alpha-interferon in human epidermoid cancer cells
No full textInhibition of Sp1 activity by a decoy PNA-DNA chimera prevents urokinase receptor expression and migration of breast cancer cells.
No full textSp1 regulates the activation of many genes involved in tumor growth, apoptosis, and angiogenesis. We have previously shown the
involvement of Sp1 in the up-regulation of urokinase receptor (uPAR) expression, a key molecule in tumor invasion and metastasis. Here,
we investigated whether a marked down-regulation of Sp1 activity may inhibit uPAR expression and migration ability of MDA-MB-231
breast cancer cells. To this end, we tested the decoy ability of a novel peptide nucleic acid (PNA)–DNA chimera which carries a central
DNA strand, containing Sp1-binding sequence, covalently linked to two PNA fragments at both ends (PNA–DNA–PNA, PDP). The
chimera was synthesized, annealed with complementary DNA (PDP–DNA), and then tested for its ability to bind Sp1 both in vitro and in
living MDA-MB-231 breast cancer cells in the presence of urokinase (uPA). This PDP–DNA decoy molecule efficiently competes for the
binding to endogenous Sp1 in nuclear extracts, and upon transfection with liposomal vectors, causes a marked decrease of available Sp1 in
both untreated and uPA-treated MDA-MB-231 cells. Accordingly, both uPA-dependent enhancement of uPAR expression and cell
migration were strongly reduced in transfected cells. Interestingly, a detectable inhibitory effect is also observed in breast cancer cells
exposed to PDP–DNA in the absence of transfection reagents. Finally, the inhibitory effect of PDP–DNA appeared to be stronger than that
observed with oligonucleotides carrying Sp1 consensus sequence. Our findings show that this novel PNA–DNA chimera, containing Sp1
consensus sequence, effectively inhibits Sp1 activity, uPAR expression, and motility of breast cancer cells indicating its potential
therapeutic use to prevent tumor dissemination
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