Autophagy facilitates lung adenocarcinoma resistance to cisplatin treatment by activation of AMPK/mTOR signaling pathway
Tao Wu,1 Min-Cong Wang,1 Li Jing,1 Zhi-Yan Liu,2 Hui Guo,1 Ying Liu,3 Yi-Yang Bai,1 Yang-Zi Cheng,1 Ke-Jun Nan,1 Xuan Liang1 1Department of Medical Oncology, The First Affiliated Hospital of Xi’an Jiaotong University, 2Department of Respiratory Medicine, Xi’an Central Hospital,...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Dove Medical Press
2015-12-01
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| Series: | Drug Design, Development and Therapy |
| Subjects: | |
| Online Access: | https://www.dovepress.com/autophagy-facilitates-lung-adenocarcinoma-resistance-to-cisplatin-trea-peer-reviewed-article-DDDT |
| _version_ | 1818131400016003072 |
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| author | Wu T Wang MC Jing L Liu ZY Guo H Liu Y Bai YY Cheng YZ Nan KJ Liang X |
| author_facet | Wu T Wang MC Jing L Liu ZY Guo H Liu Y Bai YY Cheng YZ Nan KJ Liang X |
| author_sort | Wu T |
| collection | DOAJ |
| description | Tao Wu,1 Min-Cong Wang,1 Li Jing,1 Zhi-Yan Liu,2 Hui Guo,1 Ying Liu,3 Yi-Yang Bai,1 Yang-Zi Cheng,1 Ke-Jun Nan,1 Xuan Liang1 1Department of Medical Oncology, The First Affiliated Hospital of Xi’an Jiaotong University, 2Department of Respiratory Medicine, Xi’an Central Hospital, 3Department of Medical Oncology, Shaanxi Provincial People’s Hospital, Xi’an, Shaanxi, People’s Republic of China Abstract: Resistance to cisplatin-based therapy is a major challenge in the control of lung cancer progression. However, the underlying mechanisms remain largely unclear. Autophagy is closely associated with resistance to lung cancer therapy, but the function of autophagy in cisplatin treatment is still controversial. Here, we investigated whether autophagy was involved in lung adenocarcinoma resistance to cisplatin and further elucidated the underlying molecular mechanisms. Cisplatin-refractory lung adenocarcinoma cells increased autophagic vacuole formation detected by monodansylcadaverine staining. When exposed to cisplatin, lung adenocarcinoma cells demonstrated increased levels of autophagy detected by MAP1A/1B LC3B and mammalian homologue of yeast Atg6 (Beclin-1) expression using Western blot analysis. Activation of cisplatin-induced autophagic flux was increased by using chloroquine (CQ), which can accumulate LC3B-II protein and increase punctate distribution of LC3B localization. The combination of cisplatin with CQ was more potent than cisplatin alone in inhibiting lung adenocarcinoma cell growth, which also increased cisplatin-induced apoptosis. Compared to cisplatin treatment alone, the combination of cisplatin and CQ decreased p-AMPK and increased p-mTOR protein expressions, in addition, the AMPK inhibitor Compound C plus cisplatin downregulated p-AMPK and upregulated p-mTOR as well as depressed LC3B cleavage. These findings demonstrate that activation of autophagy is a hallmark of cisplatin exposure in human lung adenocarcinoma cells, and that there is a cisplatin-induced autophagic response via activation of the AMPK/mTOR signaling pathway. We speculate that autophagy can be used as a novel therapeutic target to overcome cisplatin-resistant lung adenocarcinoma. Keywords: autophagy, lung cancer, A549 cells, A549/DDP cells, chemoresistance, AMPK, chloroquine |
| first_indexed | 2024-12-11T08:20:20Z |
| format | Article |
| id | doaj.art-c4a72c05b07347ab935f7789f820ac0c |
| institution | Directory Open Access Journal |
| issn | 1177-8881 |
| language | English |
| last_indexed | 2024-12-11T08:20:20Z |
| publishDate | 2015-12-01 |
| publisher | Dove Medical Press |
| record_format | Article |
| series | Drug Design, Development and Therapy |
| spelling | doaj.art-c4a72c05b07347ab935f7789f820ac0c2022-12-22T01:14:40ZengDove Medical PressDrug Design, Development and Therapy1177-88812015-12-012015Issue 16421643124955Autophagy facilitates lung adenocarcinoma resistance to cisplatin treatment by activation of AMPK/mTOR signaling pathwayWu TWang MCJing LLiu ZYGuo HLiu YBai YYCheng YZNan KJLiang XTao Wu,1 Min-Cong Wang,1 Li Jing,1 Zhi-Yan Liu,2 Hui Guo,1 Ying Liu,3 Yi-Yang Bai,1 Yang-Zi Cheng,1 Ke-Jun Nan,1 Xuan Liang1 1Department of Medical Oncology, The First Affiliated Hospital of Xi’an Jiaotong University, 2Department of Respiratory Medicine, Xi’an Central Hospital, 3Department of Medical Oncology, Shaanxi Provincial People’s Hospital, Xi’an, Shaanxi, People’s Republic of China Abstract: Resistance to cisplatin-based therapy is a major challenge in the control of lung cancer progression. However, the underlying mechanisms remain largely unclear. Autophagy is closely associated with resistance to lung cancer therapy, but the function of autophagy in cisplatin treatment is still controversial. Here, we investigated whether autophagy was involved in lung adenocarcinoma resistance to cisplatin and further elucidated the underlying molecular mechanisms. Cisplatin-refractory lung adenocarcinoma cells increased autophagic vacuole formation detected by monodansylcadaverine staining. When exposed to cisplatin, lung adenocarcinoma cells demonstrated increased levels of autophagy detected by MAP1A/1B LC3B and mammalian homologue of yeast Atg6 (Beclin-1) expression using Western blot analysis. Activation of cisplatin-induced autophagic flux was increased by using chloroquine (CQ), which can accumulate LC3B-II protein and increase punctate distribution of LC3B localization. The combination of cisplatin with CQ was more potent than cisplatin alone in inhibiting lung adenocarcinoma cell growth, which also increased cisplatin-induced apoptosis. Compared to cisplatin treatment alone, the combination of cisplatin and CQ decreased p-AMPK and increased p-mTOR protein expressions, in addition, the AMPK inhibitor Compound C plus cisplatin downregulated p-AMPK and upregulated p-mTOR as well as depressed LC3B cleavage. These findings demonstrate that activation of autophagy is a hallmark of cisplatin exposure in human lung adenocarcinoma cells, and that there is a cisplatin-induced autophagic response via activation of the AMPK/mTOR signaling pathway. We speculate that autophagy can be used as a novel therapeutic target to overcome cisplatin-resistant lung adenocarcinoma. Keywords: autophagy, lung cancer, A549 cells, A549/DDP cells, chemoresistance, AMPK, chloroquinehttps://www.dovepress.com/autophagy-facilitates-lung-adenocarcinoma-resistance-to-cisplatin-trea-peer-reviewed-article-DDDTAutophagylung adenocarcinomacisplatin-resistanceAMPK/mTORchlororquine |
| spellingShingle | Wu T Wang MC Jing L Liu ZY Guo H Liu Y Bai YY Cheng YZ Nan KJ Liang X Autophagy facilitates lung adenocarcinoma resistance to cisplatin treatment by activation of AMPK/mTOR signaling pathway Drug Design, Development and Therapy Autophagy lung adenocarcinoma cisplatin-resistance AMPK/mTOR chlororquine |
| title | Autophagy facilitates lung adenocarcinoma resistance to cisplatin treatment by activation of AMPK/mTOR signaling pathway |
| title_full | Autophagy facilitates lung adenocarcinoma resistance to cisplatin treatment by activation of AMPK/mTOR signaling pathway |
| title_fullStr | Autophagy facilitates lung adenocarcinoma resistance to cisplatin treatment by activation of AMPK/mTOR signaling pathway |
| title_full_unstemmed | Autophagy facilitates lung adenocarcinoma resistance to cisplatin treatment by activation of AMPK/mTOR signaling pathway |
| title_short | Autophagy facilitates lung adenocarcinoma resistance to cisplatin treatment by activation of AMPK/mTOR signaling pathway |
| title_sort | autophagy facilitates lung adenocarcinoma resistance to cisplatin treatment by activation of ampk mtor signaling pathway |
| topic | Autophagy lung adenocarcinoma cisplatin-resistance AMPK/mTOR chlororquine |
| url | https://www.dovepress.com/autophagy-facilitates-lung-adenocarcinoma-resistance-to-cisplatin-trea-peer-reviewed-article-DDDT |
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