MHY1485 is a potent activator of mTOR, which inhibits autophagy and the fusion between autophagosomes and lysosomes[1].
MHY1485 has an inhibitory effect on the autophagic process by inhibition of fusion between autophagosomes and lysosomes leading to the accumulation of LC3II protein and enlarged autophagosomes. MHY1485 also induces mTOR activity, providing a possibility for another regulatory mechanism of autophagy by the MHY compound[2]. In the activation of mTOR in HCC cells MHY1485, gdc inhibited the autophagy activity induced by gdc by upregulating the expression of p-mTOR and downregulating the expression of LC3 and p62 [3]. MHY1485 inhibits UV-induced skin cell damages via activating mTOR-Nrf2 signaling[6].MHY1485 treatment inhibited growth and colony formation in both cell lines under irradiation and no-irradiation conditions, results that were not fully consistent with MHY1485's known role in activating mTOR signaling. Combined treatment with MHY1485 and radiation significantly increased apoptosis and senescence in tumor cells in association with oxidative stress, ER stress and p21 stabilization, compared to radiation treatment alone[5].
MHY1485 (an agonist of mTOR) significantly suppressed autophagy signaling by activating mTOR. The expression of hypoxia-inducible factor 1-alpha (HIF-1α) was increased after FSH treatment. Blocking hypoxia-inducible factor 1-alpha attenuated autophagy signaling. [4]. SN potentiated the motor ability in PD mice, promoted the survival of dopaminergic neurons, increased the protein expression level of Beclin1, LC3-II/LC3-I ratio and LC3B-positive neurons, lowered the protein expression level of p62 and inactivated PI3K/AKT/mTOR pathway in the substantia nigra tissue of mouse brains. Moreover, MHY1485 reversed the above effects of SN on PD mice via reactivating PI3K/AKT/mTOR pathway[7].
References:
[1]: Yang B, Zhou Y,et,al. ω-6 Polyunsaturated fatty acids (linoleic acid) activate both autophagy and antioxidation in a synergistic feedback loop via TOR-dependent and TOR-independent signaling pathways. Cell Death Dis. 2020 Jul 30;11(7):607. doi: 10.1038/s41419-020-02750-0. PMID: 32732901; PMCID: PMC7393504.
[2]: Choi YJ, Park YJ, et,al. Inhibitory effect of mTOR activator MHY1485 on autophagy: suppression of lysosomal fusion. PLoS One. 2012;7(8):e43418. doi: 10.1371/journal.pone.0043418. Epub 2012 Aug 22. Erratum in: PLoS One. 2013;8(1). doi:10.1371/annotation/e3163ad5-f3d8-4a21-b3e1-f2033a76f9db. PMID: 22927967; PMCID: PMC3425474.
[3]: Gao L, Lv G, et,al. Glycochenodeoxycholate promotes hepatocellular carcinoma invasion and migration by AMPK/mTOR dependent autophagy activation. Cancer Lett. 2019 Jul 10;454:215-223. doi: 10.1016/j.canlet.2019.04.009. Epub 2019 Apr 11. PMID: 30980867.
[4]: Zhou J, Yao W, et,al. Administration of follicle-stimulating hormone induces autophagy via upregulation of HIF-1α in mouse granulosa cells. Cell Death Dis. 2017 Aug 17;8(8):e3001. doi: 10.1038/cddis.2017.371. PMID: 28817115; PMCID: PMC5596559.
[5]: Sun L, Morikawa K, et,al. MHY1485 enhances X-irradiation-induced apoptosis and senescence in tumor cells. J Radiat Res. 2021 Sep 13;62(5):782-792. doi: 10.1093/jrr/rrab057. PMID: 34265852; PMCID: PMC8438247.
[6]: Yang B, Xu QY, et,al. MHY1485 ameliorates UV-induced skin cell damages via activating mTOR-Nrf2 signaling. Oncotarget. 2017 Feb 21;8(8):12775-12783. doi: 10.18632/oncotarget.14299. PMID: 28061443; PMCID: PMC5355053.
[7]: Bao X, He Y, et,al. Sinomenine exerts a neuroprotective effect on PD mouse model through inhibiting PI3K/AKT/mTOR pathway to enhance autophagy. Int J Neurosci. 2022 Jul 18:1-9. doi: 10.1080/00207454.2022.2100780. Epub ahead of print. PMID: 35815397.
MHY1485 是一种有效的 mTOR 激活剂，可抑制自噬以及自噬体与溶酶体之间的融合[1]。
MHY1485 通过抑制自噬体和溶酶体之间的融合导致 LC3II 蛋白的积累和扩大的自噬体，从而对自噬过程产生抑制作用。 MHY1485 还诱导 mTOR 活性，为 MHY 化合物[2] 的自噬的另一种调节机制提供了可能性。在HCC细胞MHY1485中mTOR的激活中，gdc通过上调p-mTOR的表达，下调LC3和p62的表达来抑制gdc诱导的自噬活性[3]。 MHY1485 通过激活 mTOR-Nrf2 信号抑制紫外线诱导的皮肤细胞损伤[6]。MHY1485 处理在辐照和非辐照条件下抑制两种细胞系的生长和集落形成，结果不完全一致MHY1485 在激活 mTOR 信号传导中的已知作用。与单独放疗相比，MHY1485 和放疗联合治疗显着增加了与氧化应激、ER 应激和 p21 稳定相关的肿瘤细胞凋亡和衰老[5]。
MHY1485（mTOR 的激动剂）通过激活 mTOR 显着抑制自噬信号。 FSH 处理后缺氧诱导因子 1-α (HIF-1α) 的表达增加。阻断缺氧诱导因子 1-alpha 可减弱自噬信号。 [4]。 SN 增强 PD 小鼠的运动能力，促进多巴胺能神经元的存活，增加 Beclin1、LC3-II/LC3-I 比率和 LC3B 阳性神经元的蛋白表达水平，降低 p62 的蛋白表达水平并使 PI3K/AKT 失活/mTOR 通路在小鼠大脑的黑质组织中。此外，MHY1485通过重新激活PI3K/AKT/mTOR信号通路逆转了SN对PD小鼠的上述影响[7]。