Dual targeting of NUAK1 and ULK1 using the multitargeted inhibitor MRT68921 exerts potent antitumor activities

Chen, Yiran; Xie, Xiaoling; Chun-sheng, Wang; Hu, Ya-Han; Zhang, Honghao; Zhang, Lenghe; Tu, Sanfang; He, Yanjie; Li, Yuhua

doi:10.1038/s41419-020-02885-0

Cited by 24 publications

(23 citation statements)

References 30 publications

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“…SBI-0206965 and MRT-68921 are inhibitors of a serine/threonine kinase, ULK-1, which can prevent autophagosome formation, and can inhibit several additional kinases 29 . Chen et al reported that in addition to ULK1, MRT-68921 can inhibit NUAK family SNF1-like kinase 1 (NUAK1), an anti-oxidant molecule, and eventually can exert effective cytotoxicity in various solid cancer cell lines 30 . Moreover, Hwang et al recently reported that both SBI-0206965 and MRT-68921 could induce degradation of internal tandem duplication mutations in the FLT3 tyrosine kinase receptor (FLT3-ITD) protein, thereby exerting cytotoxicity in FLT-ITD AML cells 31 .…”

Section: Discussionmentioning

confidence: 99%

Cytoplasmic DNA accumulation preferentially triggers cell death of myeloid leukemia cells by interacting with intracellular DNA sensing pathway

et al. 2021

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Accumulating evidence indicates the presence of cytoplasmic DNAs in various types of malignant cells, and its involvement in anti-cancer drug- or radiotherapy-mediated DNA damage response and replication stress. However, the pathophysiological roles of cytoplasmic DNAs in leukemias remain largely unknown. We observed that during hematopoietic stem cell transplantation (HSCT) in mouse myeloid leukemia models, double-stranded (ds)DNAs were constitutively secreted in the form of extracellular vesicles (EVs) from myeloid leukemia cells and were transferred to the donor cells to dampen their hematopoietic capabilities. Subsequent analysis of cytoplasmic DNA dynamics in leukemia cells revealed that autophagy regulated cytoplasmic dsDNA accumulation and subsequent redistribution into EVs. Moreover, accumulated cytoplasmic dsDNAs activated STING pathway, thereby reducing leukemia cell viability through reactive oxygen species (ROS) generation. Pharmaceutical inhibition of autophagosome formation induced cytoplasmic DNA accumulation, eventually triggering cytoplasmic DNA sensing pathways to exert cytotoxicity, preferentially in leukemia cells. Thus, manipulation of cytoplasmic dsDNA dynamics can be a novel and potent therapeutic strategy for myeloid leukemias.

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Section: Discussionmentioning

confidence: 99%

Cytoplasmic DNA accumulation preferentially triggers cell death of myeloid leukemia cells by interacting with intracellular DNA sensing pathway

et al. 2021

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“…Recently, Chen et al. demonstrated that simultaneous inhibition of ULK1 (MRT68921) with NUAK1 (also known as ARK1) induces apoptosis in various cancer types ( 31 ).…”

Section: Impact Of Inhibiting the Initiation And Nucleation Steps Onmentioning

confidence: 99%

Targeting Cytoprotective Autophagy to Enhance Anticancer Therapies

et al. 2021

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Autophagy is a highly regulated multi-step process that occurs at the basal level in almost all cells. Although the deregulation of the autophagy process has been described in several pathologies, the role of autophagy in cancer as a cytoprotective mechanism is currently well established and supported by experimental and clinical evidence. Our understanding of the molecular mechanism of the autophagy process has largely contributed to defining how we can harness this process to improve the benefit of cancer therapies. While the role of autophagy in tumor resistance to chemotherapy is extensively documented, emerging data point toward autophagy as a mechanism of cancer resistance to radiotherapy, targeted therapy, and immunotherapy. Therefore, manipulating autophagy has emerged as a promising strategy to overcome tumor resistance to various anti-cancer therapies, and autophagy modulators are currently evaluated in combination therapies in several clinical trials. In this review, we will summarize our current knowledge of the impact of genetically and pharmacologically modulating autophagy genes and proteins, involved in the different steps of the autophagy process, on the therapeutic benefit of various cancer therapies. We will also briefly discuss the challenges and limitations to developing potent and selective autophagy inhibitors that could be used in ongoing clinical trials.

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“…MAPK1/3 kinase-dependent ULK1 degradation attenuated mitophagy [ 29 ]. Moreover, antioxidant therapy induced elevated ROS levels to activate ULK1 pathway to promote protective autophagy and ULK1-dependent mitophagy [ 30 ]. However, how the ULK1 complex is regulated to trigger mitophagy induction is not clear.…”

Section: Discussionmentioning

confidence: 99%

The combination of nuclear receptor NR1D1 and ULK1 promotes mitophagy in adipocytes to ameliorate obesity

Pan

2022

Adipocyte

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Obesity is a severe disease worldwide. Mitochondrial autophagy (mitophagy) may be related to metabolic abnormalities in obese individuals, but the mechanism is still unclear. We aimed to investigate whether nuclear receptors NR1D1 and ULK1 influence obesity by affecting mitophagy. In vitro model was established by inducing 3T3-L1 cells differentiation. MTT was detected cell viability. ELISA was tested triglyceride (TG). Oil red O staining was performed to detect lipid droplets. Flow cytometry was measured mtROS. ChIP and Dual-luciferase reporter assay were verified NR1D1 bind to ULK1. LC3 level was detected by IF. After differentiation medium treatment, cell viability was decreased, TG content and lipid droplets were increased Moreover, NR1D1 expression was reduced in Model group. NR1D1 overexpression was increased cell viability, reduced TG content and lipid droplets. Subsequently, NR1D1 inhibited TOM20 and mtROS, whereas, Parkin and PINK1 were accelerated. NR1D1 overexpression facilitated LC3 expression, whereas ULK1 knockdown was reversed the effect of NR1D1 overexpression. Liensinine also reversed the effect of NR1D1 overexpression, that is, cell viability was reduced, mtROS, TG content and lipid droplets were increased. The combination of nuclear receptor NR1D1 and ULK1 promoted mitophagy in adipocytes to alleviate obesity, which provided new target and strategy for obesity treatment. Abbreviations : Mitochondrial autophagy (mitophagy), triglyceride (TG), Uncoordinated-51 like autophagy activating kinase 1 (ULK1), Nuclear receptor subfamily 1 group D member 1 (NR1D1), American Type Culture Collection (ATCC), fetal bovine serum (FBS), 3-isobutyl-1-methylxanthine (IBMX), dexamethasone (DEX), short hairpin RNA ULK1 (sh-ULK1), wild-type (WT), mutant (MUT), Enzyme-linked immunosorbent assay (ELISA), mitochondrial reactive oxygen species (mtROS), Chromatin immunoprecipitation (ChIP), Quantitative real-time PCR (qRT-PCR), Immunofluorescence (IF), standard deviation (SD).

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Dual targeting of NUAK1 and ULK1 using the multitargeted inhibitor MRT68921 exerts potent antitumor activities

Cited by 24 publications

References 30 publications

Cytoplasmic DNA accumulation preferentially triggers cell death of myeloid leukemia cells by interacting with intracellular DNA sensing pathway

Cytoplasmic DNA accumulation preferentially triggers cell death of myeloid leukemia cells by interacting with intracellular DNA sensing pathway

Targeting Cytoprotective Autophagy to Enhance Anticancer Therapies

The combination of nuclear receptor NR1D1 and ULK1 promotes mitophagy in adipocytes to ameliorate obesity

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