MHY1485

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.