Pharmacological Inhibition of ULK1 Kinase Blocks Mammalian Target of Rapamycin (mTOR)-dependent Autophagy

Petherick, Katy J.; Conway, Owen; Mpamhanga, Chido; Osborne, Simon A.; Kamal, Ahmad M.; Saxty, Barbara; Ganley, Ian G.

doi:10.1074/jbc.c114.627778

Cited by 294 publications

(212 citation statements)

References 47 publications

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“…In parallel, increasing attention has been dedicated to components of the autophagic machinery that seem to have limited roles in other processes, such as autophagy-related 4B cysteine peptidase (ATG4B; which can be targeted by NSC185058) 297 and UNC-51-like autophagy-activating kinase 1 (ULK1; which can be targeted by SBI-0206965, MRT67307 and MRT68921) 298,299 , as well as to specific autophagic pathways, including mitophagy and LC3-associated phagocytocis (LAP) 193,213 . Lys05, SAR405, NSC185058, and SBI-0206965 have been shown to mediate anticancer effects in vitro and in vivo 294,295,297 .…”

Section: Figurementioning

confidence: 99%

“…SAR405 and SBI-0206965 synergized with mTORC1 inhibitors in arresting the proliferation of human lung (H1299 and A549) and kidney (ACHN and 786-O) cells in vitro 295,298 . Conversely, the potential therapeutic activity of VPS34-IN1 (which has been characterized biochemically in human osteosarcoma U2OS cells), MRT67307 and MRT68921 (both of which have been studied for their biochemical properties in mouse embryonic fibroblasts) has not yet been tested in relevant disease models 296,299 . Thus, the actual therapeutic potential of these approaches remains largely unexplored.…”

Section: Figurementioning

confidence: 99%

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Pharmacological modulation of autophagy: therapeutic potential and persisting obstacles

Galluzzi

Pedro

Levine

et al. 2017

Nat Rev Drug Discov

716

589

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Autophagy is central to the maintenance of organismal homeostasis in both physiological and pathological situations. Accordingly, alterations in autophagy have been linked to clinically relevant conditions as diverse as cancer, neurodegeneration and cardiac disorders. Throughout the past decade, autophagy has attracted considerable attention as a target for the development of novel therapeutics. However, such efforts have not yet generated clinically viable interventions. In this Review, we discuss the therapeutic potential of autophagy modulators, analyse the obstacles that have limited their development and propose strategies that may unlock the full therapeutic potential of autophagy modulation in the clinic.

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Section: Figurementioning

confidence: 99%

Section: Figurementioning

confidence: 99%

Pharmacological modulation of autophagy: therapeutic potential and persisting obstacles

Galluzzi

Pedro

Levine

et al. 2017

Nat Rev Drug Discov

716

589

View full text Add to dashboard Cite

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“…When mTORC1 is active, it inhibits autophagy by phosphorylating both ULK1 and ATG13 (Table 1), reducing ULK1 kinase activity [11–13,22,23]. Chemical inhibition of ULK1 prevents rapamycin from triggering autophagy, demonstrating that regulation of ULK1 is a key step in autophagy induction downstream of mTORC1 inhibition [24]. When mTORC1 is inhibited under starvation conditions, it dissociates from ULK1 [12].…”

Section: Upstream Regulation Of the Ulk1 Complexmentioning

confidence: 99%

“…The past year saw several reports of ULK1 inhibitors [24,37,40,41]. Petherick et al describe the compounds MRT67307 and MRT68921, and used them to conclude that ULK1 kinase activity is important in autophagosome maturation as well as initiation.…”

Section: Substrates and Inhibitors Of The Ulk1 Complexmentioning

confidence: 99%

Structure and function of the ULK1 complex in autophagy

Lin

Hurley

2016

Current Opinion in Cell Biology

207

159

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The ULK1 complex initiates autophagosome formation, linking cellular nutrient status to downstream events in autophagy. Recent work suggests that the ULK1 complex might also be activated in selective autophagy independent of nutrient or energy status. In this review we will discuss our current understanding of how the ULK1 complex is regulated by different signals, as well as how this complex then regulates other components of the autophagy machinery. Recently obtained structural data both on ULK1 and the orthologous yeast Atg1 complex are beginning to shed light on the higher-order organization of ULK1 complex. Ultimately, these insights might make it possible to understand how cargo organization and structure recruits and regulates ULK1 in selective autophagy initiation.

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“…To confirm the involvement of the AMPK-ULK1 pathway in 6-OHDA-induced autophagy and PARK7 secretion, SH-SY5Y cells were treated with MRT68921, a specific inhibitor of ULK1 [47], as a result of which it was found that 6-OHDA-induced increase in LC3B-II levels was suppressed by co-treatment with MRT68921 (Figure 7(D)). Furthermore, 6-OHDA-induced PARK7 secretion was suppressed by co-treatment with MRT68921 (Figure 7(E)).…”

Section: Resultsmentioning

confidence: 99%

6-Hydroxydopamine induces secretion of PARK7/DJ-1 via autophagy-based unconventional secretory pathway

et al. 2018

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PARK7/DJ-1 is a Parkinson disease- and cancer-associated protein that functions as a multifunctional protein involved in gene transcription regulation and anti-oxidative defense. Although PARK7 lacks the secretory signal sequence, it is secreted and plays important physiological and pathophysiological roles. Whereas secretory proteins that lack the endoplasmic reticulum-targeting signal sequence are secreted from cells by way of what is called the unconventional secretion mechanism, the specific processes responsible for causing PARK7 to be secreted across the plasma membrane have remained unclear. In the present study, we found that PARK7 secretion was increased by treatment with 6-OHDA via the unconventional secretory pathway in human neuroblastoma SH-SY5Y cells and MEF cells. We also found that 6-OHDA-induced PARK7 secretion was suppressed in Atg5-, Atg9-, or Atg16l1-deficient MEF cells or ATG16L1 knockdown SH-SY5Y cells, indicating that the autophagy-based unconventional secretory pathway is involved in PARK7 secretion. We moreover observed that 6-OHDA-derived electrophilic quinone induced oxidative stress as indicated by a decrease in glutathione levels, and that this was suppressed by pretreatment with antioxidant NAC. We further found that NAC treatment suppressed autophagy and PARK7 secretion. We also observed that 6-OHDA-induced autophagy was associated with activation of AMPK and ULK1 via a pathway which was independent of MTOR. Collectively these results suggest that electrophilic 6-OHDA quinone enhances oxidative stress, and that this is followed by AMPK-ULK1 pathway activation and induction of secretory autophagy to produce unconventional secretion of PARK7.Abbreviations: 6-OHDA: 6-hydroxydopamine; AMPK: AMP-activated protein kinase; ATG: autophagy related; CAV1: caveolin 1; ER: endoplasmic reticulum; FN1: fibronectin 1; GSH: glutathione; IDE: insulin degrading enzyme; IL: interleukin; LDH: lactate dehydrogenase; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MEF: mouse embryonic fibroblast; MTOR: mechanistic target of rapamycin kinase; NAC: N-acetyl-L-cysteine; PARK7/DJ-1: Parkinsonism associated deglycase; PD: Parkinson disease; RPS6KB1/p70S6K: ribosomal protein S6 kinase B1; RPN1: ribophorin I; ROS: reactive oxygen species; ULK1: unc-51 like autophagy activating kinase 1; WT: wild-type

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Pharmacological Inhibition of ULK1 Kinase Blocks Mammalian Target of Rapamycin (mTOR)-dependent Autophagy

Cited by 294 publications

References 47 publications

Pharmacological modulation of autophagy: therapeutic potential and persisting obstacles

Pharmacological modulation of autophagy: therapeutic potential and persisting obstacles

Structure and function of the ULK1 complex in autophagy

6-Hydroxydopamine induces secretion of PARK7/DJ-1 via autophagy-based unconventional secretory pathway

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