Antidepressant indatraline induces autophagy and inhibits restenosis via suppression of mTOR/S6 kinase signaling pathway

Abstract

Indatraline is an antidepressive agent and a non-selective monoamine transporter inhibitor that blocks the reuptake of neurotransmitters (dopamine, serotonin, and norepinephrine). In this study, we report that indatraline induces autophagy via the suppression of mTOR/S6 kinase signaling. Autophagy induction was examined by a cell-based high content screening system using LysoTracker, which was followed by monodansylcadaverine staining and transmission electron microscope observation. Indatraline increased the number of EGFP-LC3 cells expressing autophagosomes in the cytoplasm. Conversion of LC3 was further validated by immunoblotting. Indatraline induced autophagy by affecting the AMPK/mTOR/S6K signaling axis and had no influence on the PI3K/AKT/ERK signaling. Moreover, indatraline induced autophagy in smooth muscle cells (SMCs); further, it exhibited therapeutic potential for restenosis by inhibiting SMC accumulation in a rat restenosis model. These results provide new insights into the role of monoamine transporters in autophagy regulation and identify indatraline as a novel agent for inducing autophagy.

Inhibition of autophagy enhances synergistic effects of Salidroside and anti-tumor agents against colorectal cancer

“…The molecular mechanism by which AMPK regulates autophagy has been revealed in previous reports. AMPK regulating autophagy is dependent or independent of mTOR, through AMPK-mTOR-S6 K and AMPK-ULK1 signaling pathways, respectively [ 22 , 23 ]. mTOR activity is negatively modulated by AMPK, but mTOR inhibition associates improved autophagy, that is the reason why mTOR selective inhibitor Rapamycin is usually used as autophagy agonist.…”

A rapamycin derivative, biolimus, preferentially activates autophagy in vascular smooth muscle cells

“…Instead, the biolimus-induced autophagy contributes in enhancing cell cycle arrest and consequently inhibiting neointimal hyperplasia in vivo as effectively as do sirolimus and everolimus. Similarly, we have shown that a chemical compound targeting monoamine transporter induces autophagy in VSMCs, which sufficiently inhibits neointimal hyperplasia in the injured carotid vessels 52 . In addition, we cannot exclude a possibility that the enhanced 4E-BP1 function also contributes to cytostatic effect of biolimus because the 4E-BP1 de-phosphorylation inhibits cell proliferation 53 .…”

Moderate mammalian target of rapamycin inhibition induces autophagy in HTR8/SVneo cells via O‐linked β‐N‐acetylglucosamine signaling

“…As S6 K is a well‐characterized downstream effector molecule of mTORC1, we detected the levels of S6 K phosphorylated at Thr389 for mTOR activation . LC3B‐II, Beclin1 and SNAP29 are commonly used as markers of autophagy .…”