Intranasal 15d-PGJ2 inhibits the growth of rat lactotroph pituitary neuroendocrine tumors by inducing PPARγ-dependent apoptotic and autophagic cell death

Frontiers in Neuroscience

Neuroscience

Zongyang Li¹  Weiping Li¹  Di Zhang¹  Lei Chen¹  Chuanfang Wang¹  Jihu Yang¹  Xianjian Huang¹  Xiangbao Meng²  Guodong Huang² 

[1] Department of Neurosurgery, Shenzhen Second People’s Hospital, School of Pharmaceutial Science, Health Science Center, Shenzhen University, Shenzhen, China;null;

关键词: PPARγ;    pituitary neuroendocrine tumors;    apoptosis;    autophagy;    15d-PGJ2;   

DOI  :  10.3389/fnins.2023.1109675

 received in 2022-11-28, accepted in 2023-04-21,  发布年份 2023

来源: Frontiers

【 摘 要 】

PPARγ agonists have been reported to induce cell death in pituitary neuroendocrine tumor (PitNET) cell cultures. However, the therapeutic effects of PPARγ agonists in vivo remain unclear. In the present study, we found that intranasal 15d-PGJ2, an endogenous PPARγ agonist, resulted in growth suppression of Fischer 344 rat lactotroph PitNETs induced by subcutaneous implantation with a mini-osmotic pump containing estradiol. Intranasal 15d-PGJ2 reduced the volume and weight of the pituitary gland and the level of serum prolactin (PRL) in rat lactotroph PitNETs. 15d-PGJ2 treatment attenuated pathological changes and significantly decreased the ratio of PRL/pituitary-specific transcription factor 1 (Pit-1) and estrogen receptor α (ERα)/Pit-1 double-positive cells. Moreover, 15d-PGJ2 treatment induced apoptosis in the pituitary gland characterized by an increased ratio of TUNEL-positive cells, cleavage of caspase-3, and elevated activity of caspase-3. 15d-PGJ2 treatment decreased the levels of cytokines, including TNF-α, IL-1β, and IL-6. Furthermore, 15d-PGJ2 treatment markedly increased the protein expression of PPARγ and blocked autophagic flux, as evidenced by the accumulation of LC3-II and SQSTM1/p62 and the decrease in LAMP-1 expression. Importantly, all these effects mediated by 15d-PGJ2 were abolished by cotreatment with the PPARγ antagonist GW9662. In conclusion, intranasal 15d-PGJ2 suppressed the growth of rat lactotroph PitNETs by inducing PPARγ-dependent apoptotic and autophagic cell death. Therefore, 15d-PGJ2 may be a potential new drug for lactotroph PitNETs.

【 授权许可】

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Copyright © 2023 Li, Chen, Zhang, Huang, Yang, Li, Wang, Meng and Huang.