Translational cancer research · 2025
Glutamine metabolism drives tumor aggressiveness but not chemoresistance in ovarian carcinoma cell lines.
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Hélage Siegfried, Blanc-Quintin Marie-Céline, Neveux Nathalie, Ginguay Antonin, De Bandt Jean-Pascal, Cynober Luc, Alexandre Jérôme, Goldwasser François, Dion Élisabeth
Аннотация
BACKGROUND: Glutamine, an essential nutrient for healthy cells, supports immunity and cytoprotection during anticancer treatments. However, intense glutaminolysis may promote proliferation and chemoresistance in ovarian carcinomas by activating the PI3K/AKT/mTORC1 pathway and overexpressing c-Myc. This study aimed to characterize glutamine metabolism in ovarian carcinomas and assess its impact on tumor aggressiveness and chemosensitivity, to inform nutritional supplementation or therapeutic targeting.
METHODS: Glutamine and glucose consumption, chemosensitivity to cisplatin and paclitaxel, and doubling time were analyzed in three ovarian carcinoma cell lines (ES-2, TOV-21G: clear cell; OVCAR-3: serous papillary) and primary ascites cells under varying glutamine concentrations (0.5, 1, 2, 4 mM). Expression of glutaminase, glutamate dehydrogenase 1 (GDH1), and c-Myc, as well as PI3K/AKT/mTORC1 activation, were assessed by reverse transcription-polymerase chain reaction (RT-PCR) and Western blot.
RESULTS: TOV-21G exhibited significantly higher glutamine consumption (13.3±1.3 vs. 6.5±0.3 and 7±0.5 U/mg protein, P<0.001), increased expression of glutaminase, GDH1, and c-Myc, marked PI3K/AKT/mTORC1 activation (P=0.045), and a shorter doubling time (11.5±1.5 h, P=0.04) compared to ES-2 and OVCAR-3. OVCAR-3 showed significantly greater resistance to cisplatin and paclitaxel (P=0.03). Varying glutamine concentrations did not affect chemosensitivity.
CONCLUSIONS: Intense glutaminolysis is associated with increased tumor aggressiveness, suggesting a prognostic role for 18F-(2S,4R)-4-fluoroglutamine (18F-fluoroglutamine) positron emission tomography (PET) imaging. Glutamine supplementation, without impacting chemoresistance, may mitigate iatrogenic effects, while targeting glutaminolysis offers a therapeutic perspective.
METHODS: Glutamine and glucose consumption, chemosensitivity to cisplatin and paclitaxel, and doubling time were analyzed in three ovarian carcinoma cell lines (ES-2, TOV-21G: clear cell; OVCAR-3: serous papillary) and primary ascites cells under varying glutamine concentrations (0.5, 1, 2, 4 mM). Expression of glutaminase, glutamate dehydrogenase 1 (GDH1), and c-Myc, as well as PI3K/AKT/mTORC1 activation, were assessed by reverse transcription-polymerase chain reaction (RT-PCR) and Western blot.
RESULTS: TOV-21G exhibited significantly higher glutamine consumption (13.3±1.3 vs. 6.5±0.3 and 7±0.5 U/mg protein, P<0.001), increased expression of glutaminase, GDH1, and c-Myc, marked PI3K/AKT/mTORC1 activation (P=0.045), and a shorter doubling time (11.5±1.5 h, P=0.04) compared to ES-2 and OVCAR-3. OVCAR-3 showed significantly greater resistance to cisplatin and paclitaxel (P=0.03). Varying glutamine concentrations did not affect chemosensitivity.
CONCLUSIONS: Intense glutaminolysis is associated with increased tumor aggressiveness, suggesting a prognostic role for 18F-(2S,4R)-4-fluoroglutamine (18F-fluoroglutamine) positron emission tomography (PET) imaging. Glutamine supplementation, without impacting chemoresistance, may mitigate iatrogenic effects, while targeting glutaminolysis offers a therapeutic perspective.