Pecchillo Cimmino, Tiziana (2024) Unraveling the role of FPR2 in the metabolism of lung cancer cell. [Tesi di dottorato]
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| Tipologia del documento: | Tesi di dottorato |
|---|---|
| Lingua: | English |
| Titolo: | Unraveling the role of FPR2 in the metabolism of lung cancer cell |
| Autori: | Autore Email Pecchillo Cimmino, Tiziana tiziana.pecchillocimmino@unina.it |
| Data: | 5 Marzo 2024 |
| Numero di pagine: | 123 |
| Istituzione: | Università degli Studi di Napoli Federico II |
| Dipartimento: | Medicina Molecolare e Biotecnologie Mediche |
| Dottorato: | Medicina molecolare e biotecnologie mediche |
| Ciclo di dottorato: | 36 |
| Coordinatore del Corso di dottorato: | nome email Santoro, Massimo masantor@unina.it |
| Tutor: | nome email Ammendola, Rosario [non definito] |
| Data: | 5 Marzo 2024 |
| Numero di pagine: | 123 |
| Parole chiave: | cancer metabolism, metabolic reprogramming, Warburg effect, formyl peptide receptors |
| Settori scientifico-disciplinari del MIUR: | Area 05 - Scienze biologiche > BIO/10 - Biochimica |
| Depositato il: | 20 Mar 2024 14:03 |
| Ultima modifica: | 13 Apr 2026 08:11 |
| URI: | http://www.fedoa.unina.it/id/eprint/15558 |
Abstract
Background: Formyl peptide receptors (FPRs) belong to the GPCR super-family and include three members differentially expressed (FPR1, FPR2 and FPR3) that recognize distinct ligands. FPR2 is considered the most promiscuous isoform of the family, since it can bind a wide range of synthetic or endogenous agonists, such as the peptide WKYMVm and Annexin A1 (ANXA1). By phosphoproteomic analysis, we identified several phosphoproteins uniquely phosphorylated in FPR2-stimulated CaLu-6 cells. Interestingly, we pointed out that the largest part of these phosphoproteins is involved in the regulation of energetic metabolism. Hence, we investigated the role of FPR2 in cellular metabolism. Results: We observed that WKYMVm or ANXA1 stimulation significantly inhibits Pyruvate Dehydrogenase activity by triggering PI3K/Akt-dependent PFKBP2 phosphorylation, thus directing glucose towards glycolysis. In addition, the concentration of several metabolites associated with the pentose phosphate pathway (PPP), tricarboxyl acid cycle, nucleotide synthesis, glutamine metabolism and lipid metabolism, was also significantly enhanced in FPR2-stimulated cells. Our results highlight that the binding of specific FPR2 agonists in lung cancer cells: (i) promotes NADPH production; (ii) activates the non-oxidative phase of PPP; (iii) induces the expression of ASCT2 glutamine transporter; (iv) regulates oxidative phosphorylation; (v) induces NOX-dependent de novo synthesis of pyrimidine; (vi) influences lipid metabolism. Conclusions: Collectively, these data demonstrate that FPR2 is involved in metabolic reprogramming of lung cancer cells, since its stimulation modulates glucose and glutamine metabolism, regulate mitochondrial oxidative phosphorylation and promotes biosynthetic pathways, necessary for the survival of cancer cells. Therefore, FPR2 can be considered a promising therapeutic target for novel pharmaceutical therapies to treat human tumors.
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