A Potent and Selective ULK1 Inhibitor Suppresses Autophagy and Sensitizes Cancer Cells to Nutrient Stress
| العنوان: | A Potent and Selective ULK1 Inhibitor Suppresses Autophagy and Sensitizes Cancer Cells to Nutrient Stress |
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| المؤلفون: | Ronan C. O'Hagan, Abigail R. Solitro, Mark E. Scott, Jeffrey P. MacKeigan, Stuart D. Shumway, Hakan Gunaydin, Katie R. Martin, Peter Fuller, Stephanie L. Celano |
| المصدر: | iScience iScience, Vol 8, Iss, Pp 74-84 (2018) |
| بيانات النشر: | Elsevier, 2018. |
| سنة النشر: | 2018 |
| مصطلحات موضوعية: | 0301 basic medicine, Multidisciplinary, Functional Aspects of Cell Biology, Kinase, Chemistry, Autophagy, Mutant, Regulator, Cancer, Therapeutics, ULK1, medicine.disease, Article, 3. Good health, 03 medical and health sciences, 030104 developmental biology, Tumor progression, Cancer cell, Cancer research, medicine, lcsh:Q, lcsh:Science |
| الوصف: | Summary In response to stress, cancer cells generate nutrients and energy through a cellular recycling process called autophagy, which can promote survival and tumor progression. Accordingly, autophagy inhibition has emerged as a potential cancer treatment strategy. Inhibitors targeting ULK1, an essential and early autophagy regulator, have provided proof of concept for targeting this kinase to inhibit autophagy; however, these are limited individually in their potency, selectivity, or cellular activity. In this study, we report two small molecule ULK1 inhibitors, ULK-100 and ULK-101, and establish superior potency and selectivity over a noteworthy published inhibitor. Moreover, we show that ULK-101 suppresses autophagy induction and autophagic flux in response to different stimuli. Finally, we use ULK-101 to demonstrate that ULK1 inhibition sensitizes KRAS mutant lung cancer cells to nutrient stress. ULK-101 represents a powerful molecular tool to study the role of autophagy in cancer cells and to evaluate the therapeutic potential of autophagy inhibition. Graphical Abstract Highlights • ULK-101 has improved potency and selectivity when compared with SBI-0206965 • ULK-101 inhibits both the nucleation of autophagic vesicles and turnover • ULK-101 sensitizes KRAS-driven lung cancer cells to nutrient restriction • ULK-101 is a valuable molecular tool to study the function of ULK1 and autophagy Therapeutics; Functional Aspects of Cell Biology; Cancer |
| اللغة: | English |
| تدمد: | 2589-0042 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::315b4a79e70b423e1a78cf0977eb2662Test http://europepmc.org/articles/PMC6172447Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....315b4a79e70b423e1a78cf0977eb2662 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 25890042 |
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