CircOMA1 modulates cabergoline resistance by downregulating ferroptosis in prolactinoma

Purpose: Prolactinomas are one of the most common pituitary neuroendocrine tumors (PitNETs), accounting for approximately 50% of all pituitary tumors. Dopamine agonists are the main treatment for prolactinoma, but a small number of patients are still resistant to pharmacotherapy. Recent discoveries have revealed that Ferroptosis is involved in regulating tumor drug resistance. However, the role of Ferroptosis in prolactinoma has not been reported. In this study, we aimed to explore the mechanism of a circRNA in Ferroptosis in prolactinoma.

Methods: The expression of circOMA1 in prolactinoma tissues was examined by quantitative Reverse transcription PCR (qRT-PCR). The biological function of circOMA1 was evaluated in vitro and in vivo. To explore the role of Ferroptosis in prolactinoma, we used qRT-PCR and western blotting. Glutamate-cysteine ligase, modifier subunit (GCLM) was predicted to be a direct target gene of miR-145-5p by bioinformatics analysis, which was confirmed by luciferase reporter assays.

Results: circOMA1 was overexpressed in drug-resistant prolactinoma tissues compared with sensitive prolactinoma samples. We further found that circOMA1 promoted MMQ cells growth in vivo and in vitro. In addition, GCLM was directly targeted by miR-145-5p and indirectly regulated by circOMA1. Importantly, circOMA1 induced Ferroptosis resistance through the increased expression of Nrf2, GPX4, and xCT, and circOMA1 attenuated CAB-induced Ferroptosis in MMQ cells in vivo and in vitro.

Conclusion: The present study demonstrates that circOMA1 attenuates CAB efficacy through Ferroptosis resistance and may be a new therapeutic target for the individualized treatment of DA-resistant prolactinoma patients.

Cabergoline; CircOMA1; Drug resistance; Ferroptosis; Prolactinoma.