Discovery of a novel NUAK1 inhibitor against pancreatic cancer
The novel (nua) kinase family 1 (NUAK1) is an AMPK-related kinase and its expression is associated with tumor malignancy and poor prognosis in several types of cancer, suggesting its potential as a target for cancer therapy. Therefore, the development of NUAK1-targeting inhibitors could improve ther...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2022-08-01
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| Series: | Biomedicine & Pharmacotherapy |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0753332222006308 |
| _version_ | 1811343438052851712 |
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| author | Myeong-Seong Seo Kyung Hee Jung Kewon Kim Ji Eun Lee Beom Seok Han Soyeon Ko Jae Ho Kim Sungwoo Hong So Ha Lee Soon-Sun Hong |
| author_facet | Myeong-Seong Seo Kyung Hee Jung Kewon Kim Ji Eun Lee Beom Seok Han Soyeon Ko Jae Ho Kim Sungwoo Hong So Ha Lee Soon-Sun Hong |
| author_sort | Myeong-Seong Seo |
| collection | DOAJ |
| description | The novel (nua) kinase family 1 (NUAK1) is an AMPK-related kinase and its expression is associated with tumor malignancy and poor prognosis in several types of cancer, suggesting its potential as a target for cancer therapy. Therefore, the development of NUAK1-targeting inhibitors could improve therapeutic outcomes in cancer. We synthesized KI-301670, a novel NUAK1 inhibitor, and assessed its anticancer effects and mechanism of action in pancreatic cancer. It effectively inhibited pancreatic cancer growth and proliferation, and induced cell cycle arrest, markedly G0/G1 arrest, by increasing the expression of p27 and decreasing expression of p-Rb and E2F1. Additionally, the apoptotic effect of KI-301670 was observed by an increase in cleaved PARP, TUNEL-positive cells, and annexin V cell population, as well as the release of cytochrome c via the loss of mitochondrial membrane potential. KI-301670 inhibited the migration and invasion of pancreatic cancer cells. Mechanistically, KI-301670 effectively inhibited the PI3K/AKT pathway in pancreatic cancer cells. Furthermore, it significantly attenuated tumor growth in a mouse xenograft tumor model. Our results demonstrate that a novel NUAK1 inhibitor, KI-301670, exerts anti-tumor effects by directly suppressing cancer cell growth by affecting the PI3K/AKT pathway, suggesting that it could be a novel therapeutic candidate for pancreatic cancer treatment. |
| first_indexed | 2024-04-13T19:29:24Z |
| format | Article |
| id | doaj.art-cf87912a9a5842c19ae1ef017efbe152 |
| institution | Directory Open Access Journal |
| issn | 0753-3322 |
| language | English |
| last_indexed | 2024-04-13T19:29:24Z |
| publishDate | 2022-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Biomedicine & Pharmacotherapy |
| spelling | doaj.art-cf87912a9a5842c19ae1ef017efbe1522022-12-22T02:33:15ZengElsevierBiomedicine & Pharmacotherapy0753-33222022-08-01152113241Discovery of a novel NUAK1 inhibitor against pancreatic cancerMyeong-Seong Seo0Kyung Hee Jung1Kewon Kim2Ji Eun Lee3Beom Seok Han4Soyeon Ko5Jae Ho Kim6Sungwoo Hong7So Ha Lee8Soon-Sun Hong9Department of Medicine, College of Medicine, and Program in Biomedical Science & Engineering, Inha University, 3-ga, Sinheung-dong, Jung-gu, Incheon 22332, South KoreaDepartment of Medicine, College of Medicine, and Program in Biomedical Science & Engineering, Inha University, 3-ga, Sinheung-dong, Jung-gu, Incheon 22332, South KoreaCenter for Catalytic Hydrocarbon Functionalization, Institute of Basic Science (IBS) and Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, South KoreaDepartment of Medicine, College of Medicine, and Program in Biomedical Science & Engineering, Inha University, 3-ga, Sinheung-dong, Jung-gu, Incheon 22332, South KoreaDepartment of Medicine, College of Medicine, and Program in Biomedical Science & Engineering, Inha University, 3-ga, Sinheung-dong, Jung-gu, Incheon 22332, South KoreaDepartment of Medicine, College of Medicine, and Program in Biomedical Science & Engineering, Inha University, 3-ga, Sinheung-dong, Jung-gu, Incheon 22332, South KoreaChemical Kinomics Research Center, Institute of Science and Technology, Seoul 02792, South KoreaCenter for Catalytic Hydrocarbon Functionalization, Institute of Basic Science (IBS) and Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, South Korea; Corresponding authors.Chemical Kinomics Research Center, Institute of Science and Technology, Seoul 02792, South Korea; Corresponding authors.Department of Medicine, College of Medicine, and Program in Biomedical Science & Engineering, Inha University, 3-ga, Sinheung-dong, Jung-gu, Incheon 22332, South Korea; Corresponding authors.The novel (nua) kinase family 1 (NUAK1) is an AMPK-related kinase and its expression is associated with tumor malignancy and poor prognosis in several types of cancer, suggesting its potential as a target for cancer therapy. Therefore, the development of NUAK1-targeting inhibitors could improve therapeutic outcomes in cancer. We synthesized KI-301670, a novel NUAK1 inhibitor, and assessed its anticancer effects and mechanism of action in pancreatic cancer. It effectively inhibited pancreatic cancer growth and proliferation, and induced cell cycle arrest, markedly G0/G1 arrest, by increasing the expression of p27 and decreasing expression of p-Rb and E2F1. Additionally, the apoptotic effect of KI-301670 was observed by an increase in cleaved PARP, TUNEL-positive cells, and annexin V cell population, as well as the release of cytochrome c via the loss of mitochondrial membrane potential. KI-301670 inhibited the migration and invasion of pancreatic cancer cells. Mechanistically, KI-301670 effectively inhibited the PI3K/AKT pathway in pancreatic cancer cells. Furthermore, it significantly attenuated tumor growth in a mouse xenograft tumor model. Our results demonstrate that a novel NUAK1 inhibitor, KI-301670, exerts anti-tumor effects by directly suppressing cancer cell growth by affecting the PI3K/AKT pathway, suggesting that it could be a novel therapeutic candidate for pancreatic cancer treatment.http://www.sciencedirect.com/science/article/pii/S0753332222006308ApoptosisNUAK1KI-301670Pancreatic cancerPI3K/AKT pathway |
| spellingShingle | Myeong-Seong Seo Kyung Hee Jung Kewon Kim Ji Eun Lee Beom Seok Han Soyeon Ko Jae Ho Kim Sungwoo Hong So Ha Lee Soon-Sun Hong Discovery of a novel NUAK1 inhibitor against pancreatic cancer Biomedicine & Pharmacotherapy Apoptosis NUAK1 KI-301670 Pancreatic cancer PI3K/AKT pathway |
| title | Discovery of a novel NUAK1 inhibitor against pancreatic cancer |
| title_full | Discovery of a novel NUAK1 inhibitor against pancreatic cancer |
| title_fullStr | Discovery of a novel NUAK1 inhibitor against pancreatic cancer |
| title_full_unstemmed | Discovery of a novel NUAK1 inhibitor against pancreatic cancer |
| title_short | Discovery of a novel NUAK1 inhibitor against pancreatic cancer |
| title_sort | discovery of a novel nuak1 inhibitor against pancreatic cancer |
| topic | Apoptosis NUAK1 KI-301670 Pancreatic cancer PI3K/AKT pathway |
| url | http://www.sciencedirect.com/science/article/pii/S0753332222006308 |
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