Author: Li, Jianrui ; Gu, Jianying ; Wei, Chuanyuan ; Gao, Zixu ; Yang, Yang ; Luo, Zucheng ; Yang, Yanwen ; Wang, Lu ; Zheng, Shaoluan ; Zhang, Tianyi ; Zhu, Yu ; Wei, Chenlu ; Ming, Ren ; Ding, Yiteng ; Li, Yinlam ; Xuan, Jiangying ; Hu, Qianrong ; Shen, Kangjie

AbstractMetabolic reprogramming promotes and sustains multiple steps of melanoma metastasis. Identification of key regulators of metabolic reprogramming could lead to the development of treatments for preventing and treating metastatic melanoma. In this study, we identified that tectonic family member 1 (TCTN1) promotes melanoma metastasis by increasing fatty acid oxidation (FAO). In clinical melanoma samples, high expression of TCTN1 correlated with increased metastasis and shorter patient survival. Functionally, TCTN1 promoted melanoma invasion and migration in vitro and distant metastasis in vivo and induced a mesenchymal-like phenotype switch. Mechanistically, TCTN1 acted as a protein scaffold to promote the binding of HADHA and HADHB, subunits of the mitochondrial trifunctional protein complex, thus leading to FAO activation. TCTN1-mediated FAO activated the p38/MAPK signaling pathway in melanoma cells, promoting tumor epithelial–mesenchymal transition and stemness. Molecular docking indicated that the prostaglandin F receptor agonist fluprostenol can block HADHA/HADHB binding, which was confirmed experimentally. Treatment with fluprostenol was able to inhibit TCTN1-induced melanoma invasion and metastasis. Taken together, these findings elucidate the mechanism of TCTN1-mediated promotion of melanoma metastasis and support the potential application of fluprostenol for targeted therapy of metastatic melanoma.Significance: TCTN1 activates fatty acid oxidation to induce melanoma mesenchymal phenotype switching and invasion by promoting the binding of the subunits of MTP, which can be targeted with fluprostenol to inhibit melanoma metastasis.

01 Jun 2009·Early Human DevelopmentQ4 · MEDICINE

Gender-related effects of prenatal administration of estrogen and progesterone receptor antagonists on VEGF and surfactant-proteins and on alveolarisation in the developing piglet lung

Q4 · MEDICINE

Article

Author: Frank Pohlandt ; Cordian Beyer ; Ulrich Thome ; Anne Hilgendorff ; Evangelos Kiossis ; Andreas Trotter ; Eva Kueppers ; Markus Kipp ; Judith Stuplich

BACKGROUNDVascular endothelial growth factor (VEGF) is essential for embryonic lung development and has been shown to be regulated by estradiol (E2) and progesterone (P).AIMTo investigate the effects of prenatal E2 and P withdrawal by specific receptor antagonists on the mRNA expression of VEGF, surfactant proteins (SP-B and SP-C) and on alveolarisation in lung tissue of male and female pig fetuses.METHODSFetuses from 10 sows were randomized to receive either both an intramuscular injection of the E2 receptor blocker ICI 182.780 and the P receptor blocker RTI 3021-022 (ICI+RTI, n=5) or a placebo injection (n=5) at 90 days of gestation (DOG, 115=term). After delivery by cesarean section on 114 DOG, tissue of the left lingula of the piglet's lung (28 placebo, 26 ICI+RTI) was obtained to determine the mRNA expression of VEGF, SP-B and SP-C. Lungs from 15 placebo and 14 ICI+RTI group piglets were removed and alveolar counts performed.RESULTSThe ICI+RTI group showed significantly lower SP-C mRNA expression and alveolar counts compared to the placebo group (p=0.04 and 0.03, respectively). Diminished alveolarisation in the ICI+RTI group was mainly due to the reduction of alveolar counts in male piglets (p=0.02). Within the placebo group VEGF and SP-B mRNA expression in male piglets were significantly lower compared to female piglets (p=0.01 and 0.004, respectively). ICI+RTI treatment abolished this gender-related difference.CONCLUSIONEstradiol and P antagonism affected gender-related differences of key proteins for pulmonary function and development and especially in males was associated with diminished alveolarisation.

01 Jul 2006·Pediatric ResearchQ3 · MEDICINE

Prenatal Estrogen and Progesterone Deprivation Impairs Alveolar Formation and Fluid Clearance in Newborn Piglets

Q3 · MEDICINE

Article

Author: Evangelos Kiossis ; Sabine Meggle ; Michael Ebsen ; Ludwig Maier ; Ulrich H Thome ; Andreas Trotter ; Cordian Beyer ; Eva Kueppers ; Frank Pohlandt

Exposure to high levels of estradiol (E2) and progesterone (P) derived from the fetoplacentomaternal unit during the last trimester of pregnancy may play a crucial role in prenatal lung development and immediate postnatal alveolar fluid clearance (AFC). To measure prenatal alveolar formation and postnatal amiloride-sensitive AFC after pharmacological deprivation of E2 and P in utero, fetuses from five sows received an intramuscular depot injection of the E2 receptor blocker ICI 182.780 (ICI) and the P receptor blocker RTI 3021-022 (RTI) and fetuses of five other sows received a placebo injection (control group) during a laparotomy at 90 d of gestation (term gestation, 115 d). Piglets were delivered by cesarean section on d 114 of gestation. Of 95 live-born piglets, 35 were mechanically ventilated. The airways of the right lower lobe were isolated by a balloon catheter wedged in the bronchus and 5% albumin in 0.9% NaCl with or without 1 mmol/L amiloride was instilled. Amiloride-sensitive AFC was calculated from the protein concentration changes in fluid recovered after 120 min as the percentage of absorbed fluid. Lungs were removed under standardized conditions to perform alveolar counts. Prenatal treatment with ICI and RTI resulted in a significantly lower amiloride-sensitive AFC (median, 31%; min-max, -4-58) than placebo (74%, 18-231). Median alveolar counts per visual field were significantly lower in piglets that were exposed to ICI and RTI (38, 21-78) compared with placebo (56, 32-113). We conclude that prenatal E2 and P deprivation significantly impaired alveolar formation and amiloride-sensitive AFC.

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Indication	Highest Phase	Country/Location	Organization	Date
Kidney Diseases, Cystic	Preclinical	FR	Universite Paris Cite	03 May 2022

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