Laboratory of Therapeutic Innovation (UMR 7200), CNRS/University of Strasbourg, Faculty of Pharmacy, Illkirch, France; LCIMN Laboratory, Faculty of Technology, University Ferhat Abbas Sétif, Algeria.
Laboratory of Oncology and Experimental Surgery and Nuclear Medicine Department, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.
Eur J Med Chem. 2018 Jul 15;155:880-888. doi: 10.1016/j.ejmech.2018.06.052. Epub 2018 Jun 23.
Prohibitins 1 and 2 (PHB1/2) are scaffold proteins that are involved in both melanogenesis and oncogenic pathways. We hypothesized that a PHB1 ligand, melanogenin, may display anti-cancer effects in addition to its known melanogenic activity in melanocytes. Here, we disclose a convenient synthesis of melanogenin, and its analogs. We found that, among 57 new melanogenin analogs, two (Mel9 and Mel41) significantly promoted both melanogenesis in melanocytes by activating one of the PHB2-interacting proteins, microtubule-associated protein light chain 3 (LC3), and upregulating the expression of microphthalmia associated transcription factor (MITF). These analogs also activate ERK. Besides, in addition to their promelanogenic activities, we uncovered that melanogenin and its active analogs induce apoptosis in several cancer cell lines, including melanoma cells, and that this effect is caused by an inhibition of AKT survival pathway. Our findings present a new putative function for PHBs as regulators of LC3/ERK/MITF melanogenic signaling, and suggest that Mel9 and Mel41 may provide the basis for the development of new drugs candidates to treat melanoma and other types of cancers.
抑素 1 和 2（PHB1/2）是支架蛋白，参与黑色素生成和致癌途径。我们假设 PHB1 配体黑素原除了在黑色素细胞中具有已知的黑色素生成活性外，还可能具有抗癌作用。在这里，我们公开了一种方便的黑素原及其类似物的合成方法。我们发现，在 57 种新的黑素原类似物中，有两种（Mel9 和 Mel41）通过激活 PHB2 相互作用蛋白之一微管相关蛋白轻链 3（LC3）并上调小眼畸形相关转录因子（MITF）的表达，显著促进黑色素细胞中的黑色素生成。这些类似物还能激活 ERK。此外，除了它们的促黑色素生成活性外，我们还发现黑素原及其活性类似物在几种癌细胞系中诱导细胞凋亡，包括黑色素瘤细胞，这种作用是通过抑制 AKT 存活途径引起的。我们的研究结果提出了 PHB 作为 LC3/ERK/MITF 黑色素生成信号的调节剂的新功能，并表明 Mel9 和 Mel41 可能为开发治疗黑色素瘤和其他类型癌症的新药提供基础。
