Zhang Yichao, Wang Meng, Ji Chenxing, Chen Zhengyuan, Yang Hui, Wang Lei, Yu Yifei, Qiao Nidan, Ma Zengyi, Ye Zhao, Shao Xiaoqing, Liu Wenjuan, Wang Yi, Gong Wei, Melnikov Vladimir, Hu Lydia, Lee Eun Jig, Ye Hongying, Wang Yongfei, Li Yiming, He Min, Zhao Yao, Zhang Zhaoyun
Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai 200040, China.
Department of Endocrinology and Metabolism, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai 200040, China.
iScience. 2021 Aug 14;24(9):102983. doi: 10.1016/j.isci.2021.102983. eCollection 2021 Sep 24.
Rosiglitazone, a synthetic peroxisome proliferator-activated receptor γ (PPARγ) ligand, has been reported to reduce growth hormone (GH) and insulin-like growth factor-1 (IGF-1) in 10 patients with acromegaly. However, the mechanisms remain unknown. Here, we reveal that PPARγ directly enhances 15-hydroxyprostaglandin dehydrogenase (15-PGDH) expression, whose expression is decreased and negatively correlates with tumor size in acromegaly. Rosiglitazone decreases GH production and promotes apoptosis and autophagy in GH3 and primary somatotroph adenoma cells and suppresses hepatic GH receptor (GHR) expression and IGF-1 secretion in HepG2 cells. Activating the PGE2/cAMP/PKA pathway directly increases GHR expression. Rosiglitazone suppresses tumor growth and decreases GH and IGF-1 levels in mice inoculated subcutaneously with GH3 cells. The above effects are all dependent on 15-PGDH expression. Rosiglitazone as monotherapy effectively decreases GH and IGF-1 levels in all nineteen patients with active acromegaly. Evidence suggests that rosiglitazone may be an alternative pharmacological approach for acromegaly by targeting both pituitary adenomas and liver.
罗格列酮是一种合成的过氧化物酶体增殖物激活受体γ（PPARγ）配体，据报道，它可降低10例肢端肥大症患者的生长激素（GH）和胰岛素样生长因子-1（IGF-1）水平。然而，其机制尚不清楚。在此，我们发现PPARγ直接增强15-羟基前列腺素脱氢酶（15-PGDH）的表达，在肢端肥大症中，该酶的表达降低且与肿瘤大小呈负相关。罗格列酮可降低GH3细胞和原代生长激素腺瘤细胞中GH的产生，促进细胞凋亡和自噬，并抑制HepG2细胞中肝脏生长激素受体（GHR）的表达和IGF-1的分泌。激活PGE2/cAMP/PKA信号通路可直接增加GHR的表达。罗格列酮可抑制皮下接种GH3细胞的小鼠的肿瘤生长，并降低其GH和IGF-1水平。上述所有效应均依赖于15-PGDH的表达。罗格列酮单药治疗可有效降低所有19例活动性肢端肥大症患者的GH和IGF-1水平。有证据表明，罗格列酮可能是一种通过靶向垂体腺瘤和肝脏来治疗肢端肥大症的替代药物治疗方法。
