Background: Uncoordinated 51-like kinase 1 (ULK1) plays a vital role in autophagy. ULK1 dysregulation has recently been found in several human cancers.
Methods: mRNA expression levels of ULK1 and clinical information were analysed from The Cancer Genome Atlas data. ULK1 expression levels were verified in 36 paired fresh ccRCC tissue specimens by western blot analysis. Expression of ULK1 was knockdown by shRNA lentivirus. ULK1 activity was inhibited by SBI-0206965. The effect of inhibition of ULK1 was measured by detecting the apoptotic rate, autophagy, and the ratio of ROS and NADPH. The efficacy of SBI-0206965 in vivo was assessed by the murine xenograft model.
Findings: ULK1 mRNA expression was significantly upregulated in clear cell renal cell carcinoma (ccRCC) and overexpression of ULK1 correlated with poor outcomes. We found that ULK1 was highly expressed in 66.7% of ccRCC tumours (p < 0·05). Knockdown of ULK1 and selective inhibition of ULK1 by SBI-0206965 induced cell apoptosis in ccRCC cells. We demonstrated that SBI-0206965 triggered apoptosis by preventing autophagy and pentose phosphate pathway (PPP) flux. Furthermore, blocking the kinase activity of ULK1 with SBI-0206965 resulted in a level of anticancer effect in vivo.
Interpretation: Taken together, our results suggested that ULK1 was upregulated in ccRCC tumours and may be a potential therapeutic target. Therefore, SBI-0206965 should be further considered as an anti-ccRCC agent. FUND: This work was supported in part by The National Natural Science Foundation of China (No. 81570748) and Natural Science Foundation of Fujian Province (No. 2018J01345, 2017XQ1194).
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6116477 | PMC |
| http://dx.doi.org/10.1016/j.ebiom.2018.07.034 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Mechanism of podophyllotoxin-induced ovarian toxicity via the AMPK/TSC1/mTOR/ULK1 axis in rats on the basis of toxicological evidence chain (TEC) concept.
Ecotoxicol Environ Saf
December 2024
Luoyang Key Laboratory of Clinical Multiomics and Translational Medicine, Key Laboratory of Hereditary Rare Diseases of Health Commission of Henan Province, Henan Key Laboratory of Rare Diseases, Endocrinology and Metabolism Center, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang 471003, China. Electronic address:
Article Synopsis
- Podophyllotoxin has potential clinical benefits, such as anticancer effects, but its toxicity limits its use in medicine.
- The research involved creating a rat model to study how podophyllotoxin damages ovaries, revealing symptoms like diarrhea and bruising, alongside significant biochemical and pathological changes.
- The study found that podophyllotoxin's toxicity is linked to alterations in autophagy, specifically through the AMPK/TSC1/mTOR/ULK1 signaling pathway, providing new insights for its clinical application.
An AMBRA1, ULK1 and PP2A regulatory network regulates cytotoxic T cell differentiation via TFEB activation.
Sci Rep
December 2024
Department of Life Sciences, University of Siena, Siena, Italy.
The scaffold protein AMBRA1, which participates in the autophagy pathway, also promotes CD4 T cell differentiation to Tregs independent of autophagy through its interactor PP2A. Here we have investigated the role of AMBRA1 in CD8 T cell differentiation to cytotoxic T cells (CTL). AMBRA1 depletion in CD8 T cells was associated with impaired expression of the transcription factors RUNX3 and T-BET that drive CTL differentiation and resulted in impaired acquisition of cytotoxic potential.
View Article and Find Full Text PDFDYSREGULATION OF AUTOPHAGY IN PERIPHERAL BLOOD LEUCOCYTES IS A FACTOR IN THE DEVELOPMENT OF INFLAMMAGING IN IMMUNOCOMPROMISED PERSONS ON THE EXAMPLE OF THE SERVICEMEN OF THE DEFENSE FORCES OF UKRAINE AND CLEAN-UP WORKERS OF THE CHORNOBYL ACCIDENT.
Probl Radiac Med Radiobiol
December 2024
State Institution «National Research Center for Radiation Medicine, Hematology and Oncology of the National Academy of Medical Sciences of Ukraine», 53 Yuriia Illienka Str., Kyiv, 04050, Ukraine.
Objective: To assess the functional state and age-related characteristics of autophagy in peripheral blood leukocytes as a risk factor for the development of inflammaging using the example of the servicemen of the DefenseForces of Ukraine and clean-up workers of the Chornobyl accident.
Materials And Methods: A total of 103 male patients aged 28-77 (56,48 ∓ 9,05) years were examined. They included: the main group - 23 servicemen of the Defense Forces of Ukraine aged 44-59 (50,21 ∓ 5,13) years; the comparison group - 57 clean-up workers of the Chornobyl accident aged 56-63 (60,31 ∓ 1,78) years; and the control group -23 civilians aged 28-77 (53,26 ∓ 15,98) years.
Oscillatory autophagy induction is enabled by an updated AMPK-ULK1 regulatory wiring.
PLoS One
December 2024
Department of Genetics, ELTE Eötvös Loránd University, Budapest, Hungary.
Autophagy-dependent survival relies on a crucial oscillatory response during cellular stress. Although oscillatory behaviour is typically associated with processes like the cell cycle or circadian rhythm, emerging experimental and theoretical evidence suggests that such periodic dynamics may explain conflicting experimental results in autophagy research. In this study, we demonstrate that oscillatory behaviour in the regulation of the non-selective, stress-induced macroautophagy arises from a series of interlinked negative and positive feedback loops within the mTORC1-AMPK-ULK1 regulatory triangle.
View Article and Find Full Text PDFRegulation of N-degron recognin-mediated autophagy by the SARS-CoV-2 PLpro ubiquitin deconjugase.
Autophagy
January 2025
Department of Cell and Molecular Biology, Karolinska Institutet, Solna, Sweden.
Viral proteases play critical roles in the host cell and immune remodeling that allows virus production. The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) papain-like protease (PLpro) encoded in the large nonstructural protein 3 (Nsp3) also possesses isopeptidase activity with specificity for ubiquitin and ISG15 conjugates. Here, we interrogated the cellular interactome of the SARS-CoV-2 PLpro catalytic domain to gain insight into the putative substrates and cellular functions affected by the viral deubiquitinase.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!