Fiedor E, Gregoraszczuk E L
Department of Physiology and Toxicology of Reproduction, Institute of Zoology and Biomedical Research, Jagiellonian University, Gronostajowa 9, 30-387, Kraków, Poland.
Cancer Chemother Pharmacol. 2017 Oct;80(4):815-827. doi: 10.1007/s00280-017-3423-5. Epub 2017 Aug 31.
There are no data showing a direct correlation between obesity and increased blood leptin levels with folliculoma. Moreover, folliculoma is not the best studied among other ovarian cancer types. We investigated whether oestradiol can modulate ObR expression in some oestrogen-responsive tissues and that leptin exerts its activity not only via the leptin receptor but also through cross talk with other signalling systems. We hypothesise that blocking ObR expression could be a novel treatment for gonadal ovarian cancer.
We evaluated the effect of SHLA, Lan1 and Lan2 blockers on cell proliferation (BrdU incorporation assay), ObR and ERα/β gene expression (qPCR), oestradiol secretion (ELISA) and cell cycle protein expression (Western blot) in the non-cancerous cell line HGrC1 and two granulosa cancer cell lines: the juvenile form (COV434) and the adult form (KGN).
ObR gene expression in cancer cell lines was 50% higher than in the non-cancer cells. Lan-1 and Lan-2 decreased ObR expression in COV434, while it had no effect in KGN cells. Higher ERβ expression in non-cancer and higher ERα expression in both cancer cell lines was noted. SHLA and Lan-1 changed the ratio towards greater expression of ERβ, characteristic of non-cancer granulosa cells. All ObR antagonists in HCrC1 and KGN but only Lan-2 in COV434 reversed leptin-stimulated proliferation. In both non-cancer and cancer granulosa cells, leptin acts as a cyclinD/cdk4, cyclin A/cdk2 and E2F inhibitor.
These results indicate that SHLA and Lan2 are promising leptin receptor inhibitors that can eliminate the negative effects of leptin. These compounds should be considered in further ex vivo studies on the cancer microenvironment.
尚无数据表明肥胖及血液中瘦素水平升高与卵泡瘤之间存在直接关联。此外，在其他卵巢癌类型中，卵泡瘤的研究并不充分。我们研究了雌二醇是否能调节某些雌激素反应性组织中ObR的表达，以及瘦素不仅通过瘦素受体发挥作用，还通过与其他信号系统的相互作用来发挥其活性。我们假设阻断ObR的表达可能是一种治疗性腺性卵巢癌的新方法。
我们评估了SHLA、Lan1和Lan2阻滞剂对非癌细胞系HGrC1以及两种颗粒细胞癌细胞系：幼年型（COV434）和成年型（KGN）的细胞增殖（BrdU掺入试验）、ObR和ERα/β基因表达（qPCR）、雌二醇分泌（ELISA）以及细胞周期蛋白表达（蛋白质印迹法）的影响。
癌细胞系中ObR基因表达比非癌细胞高50%。Lan-1和Lan-2降低了COV434中ObR的表达，但对KGN细胞无影响。观察到非癌细胞中ERβ表达较高，而两种癌细胞系中ERα表达较高。SHLA和Lan-1使ERβ的表达比例向非癌颗粒细胞特有的更高表达方向转变。HCrC1和KGN中的所有ObR拮抗剂，但COV434中只有Lan-2逆转了瘦素刺激的增殖。在非癌和癌性颗粒细胞中，瘦素均作为细胞周期蛋白D/细胞周期蛋白依赖性激酶4、细胞周期蛋白A/细胞周期蛋白依赖性激酶2和E2F的抑制剂。
这些结果表明，SHLA和Lan2是有前景的瘦素受体抑制剂，可消除瘦素的负面影响。在进一步关于癌症微环境的体外研究中应考虑这些化合物。
