AMPK activation by ASP4132 inhibits non-small cell lung cancer cell growth
Abstract Activation of adenosine monophosphate-activated protein kinase (AMPK) is able to produce significant anti-non-small cell lung cancer (NSCLC) cell activity. ASP4132 is an orally active and highly effective AMPK activator. The current study tested its activity against NSCLC cells. In primary...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2021-04-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-021-03655-2 |
| _version_ | 1818937497593315328 |
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| author | Ying-chen Xia Jian-hua Zha Yong-Hua Sang Hui Yin Guo-qiu Xu Jie Zhen Yan Zhang Ben-tong Yu |
| author_facet | Ying-chen Xia Jian-hua Zha Yong-Hua Sang Hui Yin Guo-qiu Xu Jie Zhen Yan Zhang Ben-tong Yu |
| author_sort | Ying-chen Xia |
| collection | DOAJ |
| description | Abstract Activation of adenosine monophosphate-activated protein kinase (AMPK) is able to produce significant anti-non-small cell lung cancer (NSCLC) cell activity. ASP4132 is an orally active and highly effective AMPK activator. The current study tested its activity against NSCLC cells. In primary NSCLC cells and established cell lines (A549 and NCI-H1944) ASP4132 potently inhibited cell growth, proliferation and cell cycle progression as well as cell migration and invasion. Robust apoptosis activation was detected in ASP4132-treated NSCLC cells. Furthermore, ASP4132 treatment in NSCLC cells induced programmed necrosis, causing mitochondrial p53-cyclophilin D (CyPD)-adenine nucleotide translocase 1 (ANT1) association, mitochondrial depolarization and medium lactate dehydrogenase release. In NSCLC cells ASP4132 activated AMPK signaling, induced AMPKα1-ACC phosphorylation and increased AMPK activity. Furthermore, AMPK downstream events, including mTORC1 inhibition, receptor tyrosine kinases (PDGFRα and EGFR) degradation, Akt inhibition and autophagy induction, were detected in ASP4132-treated NSCLC cells. Importantly, AMPK inactivation by AMPKα1 shRNA, knockout (using CRISPR/Cas9 strategy) or dominant negative mutation (T172A) almost reversed ASP4132-induced anti-NSCLC cell activity. Conversely, a constitutively active AMPKα1 (T172D) mimicked and abolished ASP4132-induced actions in NSCLC cells. In vivo, oral administration of a single dose of ASP4132 largely inhibited NSCLC xenograft growth in SCID mice. AMPK activation, mTORC1 inhibition and EGFR-PDGFRα degradation as well as Akt inhibition and autophagy induction were detected in ASP4132-treated NSCLC xenograft tumor tissues. Together, activation of AMPK by ASP4132 potently inhibits NSCLC cell growth in vitro and in vivo. |
| first_indexed | 2024-12-20T05:52:54Z |
| format | Article |
| id | doaj.art-450def1ccc064977af2db9f37da7d070 |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-12-20T05:52:54Z |
| publishDate | 2021-04-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-450def1ccc064977af2db9f37da7d0702022-12-21T19:51:07ZengNature Publishing GroupCell Death and Disease2041-48892021-04-0112411410.1038/s41419-021-03655-2AMPK activation by ASP4132 inhibits non-small cell lung cancer cell growthYing-chen Xia0Jian-hua Zha1Yong-Hua Sang2Hui Yin3Guo-qiu Xu4Jie Zhen5Yan Zhang6Ben-tong Yu7Department of Thoracic Surgery, The First Affiliated Hospital of Nanchang UniversityDepartment of Thoracic Surgery, The First Affiliated Hospital of Nanchang UniversityDepartment of Thoracic Surgery, The Second affiliated Hospital of Soochow UniversityDepartment of Thoracic Surgery, The First Affiliated Hospital of Nanchang UniversityDepartment of Thoracic Surgery, The First Affiliated Hospital of Nanchang UniversityDepartment of Thoracic Surgery, Qidong People’s HospitalDepartment of Radiotherapy and Oncology, Affiliated Kunshan Hospital of Jiangsu UniversityDepartment of Thoracic Surgery, The First Affiliated Hospital of Nanchang UniversityAbstract Activation of adenosine monophosphate-activated protein kinase (AMPK) is able to produce significant anti-non-small cell lung cancer (NSCLC) cell activity. ASP4132 is an orally active and highly effective AMPK activator. The current study tested its activity against NSCLC cells. In primary NSCLC cells and established cell lines (A549 and NCI-H1944) ASP4132 potently inhibited cell growth, proliferation and cell cycle progression as well as cell migration and invasion. Robust apoptosis activation was detected in ASP4132-treated NSCLC cells. Furthermore, ASP4132 treatment in NSCLC cells induced programmed necrosis, causing mitochondrial p53-cyclophilin D (CyPD)-adenine nucleotide translocase 1 (ANT1) association, mitochondrial depolarization and medium lactate dehydrogenase release. In NSCLC cells ASP4132 activated AMPK signaling, induced AMPKα1-ACC phosphorylation and increased AMPK activity. Furthermore, AMPK downstream events, including mTORC1 inhibition, receptor tyrosine kinases (PDGFRα and EGFR) degradation, Akt inhibition and autophagy induction, were detected in ASP4132-treated NSCLC cells. Importantly, AMPK inactivation by AMPKα1 shRNA, knockout (using CRISPR/Cas9 strategy) or dominant negative mutation (T172A) almost reversed ASP4132-induced anti-NSCLC cell activity. Conversely, a constitutively active AMPKα1 (T172D) mimicked and abolished ASP4132-induced actions in NSCLC cells. In vivo, oral administration of a single dose of ASP4132 largely inhibited NSCLC xenograft growth in SCID mice. AMPK activation, mTORC1 inhibition and EGFR-PDGFRα degradation as well as Akt inhibition and autophagy induction were detected in ASP4132-treated NSCLC xenograft tumor tissues. Together, activation of AMPK by ASP4132 potently inhibits NSCLC cell growth in vitro and in vivo.https://doi.org/10.1038/s41419-021-03655-2 |
| spellingShingle | Ying-chen Xia Jian-hua Zha Yong-Hua Sang Hui Yin Guo-qiu Xu Jie Zhen Yan Zhang Ben-tong Yu AMPK activation by ASP4132 inhibits non-small cell lung cancer cell growth Cell Death and Disease |
| title | AMPK activation by ASP4132 inhibits non-small cell lung cancer cell growth |
| title_full | AMPK activation by ASP4132 inhibits non-small cell lung cancer cell growth |
| title_fullStr | AMPK activation by ASP4132 inhibits non-small cell lung cancer cell growth |
| title_full_unstemmed | AMPK activation by ASP4132 inhibits non-small cell lung cancer cell growth |
| title_short | AMPK activation by ASP4132 inhibits non-small cell lung cancer cell growth |
| title_sort | ampk activation by asp4132 inhibits non small cell lung cancer cell growth |
| url | https://doi.org/10.1038/s41419-021-03655-2 |
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