Pristimerin Exacerbates Cellular Injury in Conditionally Reprogrammed Patient-Derived Lung Adenocarcinoma Cells by Aggravating Mitochondrial Impairment and Endoplasmic Reticulum Stress through EphB4/CDC42/N-WASP Signaling
Lung cancer is the most common and lethal malignant disease for which the development of efficacious chemotherapeutic agents remains an urgent need. Pristimerin (PRIS), a natural bioactive component isolated from various plant species in the Celastraceae and Hippocrateaceae families, has been report...
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doaj-6832ec348aee4cba9abc9e44de4dd5b52020-11-25T03:35:13ZengHindawi LimitedOxidative Medicine and Cellular Longevity1942-09001942-09942020-01-01202010.1155/2020/74098537409853Pristimerin Exacerbates Cellular Injury in Conditionally Reprogrammed Patient-Derived Lung Adenocarcinoma Cells by Aggravating Mitochondrial Impairment and Endoplasmic Reticulum Stress through EphB4/CDC42/N-WASP SignalingYubo Tang0Yiyan Lei1Shuai Huang2Zhangyan Li3Xiangtian Chen4Honghe Luo5Chao Cheng6Jie Chen7Xuenong Zou8Xiao Chen9Department of Pharmacy, The First Affiliated Hospital, Sun Yat-sen University, 510080 Guangzhou, ChinaDepartment of Thoracic Surgery, The First Affiliated Hospital, Sun Yat-sen University, 510080 Guangzhou, ChinaDepartment of Orthopaedic Surgery, The Second Affiliated Hospital, Guangzhou Medical University, 510260 Guangzhou, ChinaDepartment of Pharmacy, The Boai Hospital of Zhongshan City, 528400 Zhongshan, ChinaDepartment of Pharmacy, The First Affiliated Hospital, Sun Yat-sen University, 510080 Guangzhou, ChinaDepartment of Thoracic Surgery, The First Affiliated Hospital, Sun Yat-sen University, 510080 Guangzhou, ChinaDepartment of Thoracic Surgery, The First Affiliated Hospital, Sun Yat-sen University, 510080 Guangzhou, ChinaDepartment of Pharmacy, The First Affiliated Hospital, Sun Yat-sen University, 510080 Guangzhou, ChinaDepartment of Orthopaedic Surgery, The First Affiliated Hospital, Sun Yat-sen University, 510080 Guangzhou, ChinaDepartment of Pharmacy, The First Affiliated Hospital, Sun Yat-sen University, 510080 Guangzhou, ChinaLung cancer is the most common and lethal malignant disease for which the development of efficacious chemotherapeutic agents remains an urgent need. Pristimerin (PRIS), a natural bioactive component isolated from various plant species in the Celastraceae and Hippocrateaceae families, has been reported to exhibit outstanding antitumor effects in several types of cells. However, the underlying mechanisms involved remain poorly understood. Here, we reported the novel finding that PRIS significantly suppressed lung cancer growth in conditionally reprogrammed patient-derived lung adenocarcinoma cells (CRLCs). We demonstrated that PRIS inhibited the cell viabilities, migrative and invaded abilities, and capillary structure formation of CRLCs. Furthermore, our results clarified that PRIS induced mitochondrial dysfunction through reactive oxygen species (ROS) generation, activation of caspase-9, caspase-3, and caspase-4, and expression of endoplasmic reticulum (ER) stress-associated proteins. Inhibition of ER stress by 4-PBA (4-phenylbutyric acid, a specific ER stress inhibitor) or CHOP siRNA transfection ameliorated PRIS-induced loss of mitochondrial membrane potential and intrinsic apoptosis. The present study also provides mechanistic evidence that PRIS suppressed the EphB4/CDC42/N-WASP signaling pathway, which is required for mitochondrial-mediated intrinsic apoptosis, activation of ER stress, and stimulation of caspase-4 induced by PRIS, and consequently resulting in suppressed cell viability, migration, and angiogenesis in CRLCs. Taken together, by providing a mechanistic insight into the modulation of ER stress-induced cell death in CRLCs by PRIS, we suggest that PRIS has a strong potential of being a new antitumor therapeutic agent with applications in the fields of human lung adenocarcinoma.http://dx.doi.org/10.1155/2020/7409853 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Yubo Tang Yiyan Lei Shuai Huang Zhangyan Li Xiangtian Chen Honghe Luo Chao Cheng Jie Chen Xuenong Zou Xiao Chen |
spellingShingle |
Yubo Tang Yiyan Lei Shuai Huang Zhangyan Li Xiangtian Chen Honghe Luo Chao Cheng Jie Chen Xuenong Zou Xiao Chen Pristimerin Exacerbates Cellular Injury in Conditionally Reprogrammed Patient-Derived Lung Adenocarcinoma Cells by Aggravating Mitochondrial Impairment and Endoplasmic Reticulum Stress through EphB4/CDC42/N-WASP Signaling Oxidative Medicine and Cellular Longevity |
author_facet |
Yubo Tang Yiyan Lei Shuai Huang Zhangyan Li Xiangtian Chen Honghe Luo Chao Cheng Jie Chen Xuenong Zou Xiao Chen |
author_sort |
Yubo Tang |
title |
Pristimerin Exacerbates Cellular Injury in Conditionally Reprogrammed Patient-Derived Lung Adenocarcinoma Cells by Aggravating Mitochondrial Impairment and Endoplasmic Reticulum Stress through EphB4/CDC42/N-WASP Signaling |
title_short |
Pristimerin Exacerbates Cellular Injury in Conditionally Reprogrammed Patient-Derived Lung Adenocarcinoma Cells by Aggravating Mitochondrial Impairment and Endoplasmic Reticulum Stress through EphB4/CDC42/N-WASP Signaling |
title_full |
Pristimerin Exacerbates Cellular Injury in Conditionally Reprogrammed Patient-Derived Lung Adenocarcinoma Cells by Aggravating Mitochondrial Impairment and Endoplasmic Reticulum Stress through EphB4/CDC42/N-WASP Signaling |
title_fullStr |
Pristimerin Exacerbates Cellular Injury in Conditionally Reprogrammed Patient-Derived Lung Adenocarcinoma Cells by Aggravating Mitochondrial Impairment and Endoplasmic Reticulum Stress through EphB4/CDC42/N-WASP Signaling |
title_full_unstemmed |
Pristimerin Exacerbates Cellular Injury in Conditionally Reprogrammed Patient-Derived Lung Adenocarcinoma Cells by Aggravating Mitochondrial Impairment and Endoplasmic Reticulum Stress through EphB4/CDC42/N-WASP Signaling |
title_sort |
pristimerin exacerbates cellular injury in conditionally reprogrammed patient-derived lung adenocarcinoma cells by aggravating mitochondrial impairment and endoplasmic reticulum stress through ephb4/cdc42/n-wasp signaling |
publisher |
Hindawi Limited |
series |
Oxidative Medicine and Cellular Longevity |
issn |
1942-0900 1942-0994 |
publishDate |
2020-01-01 |
description |
Lung cancer is the most common and lethal malignant disease for which the development of efficacious chemotherapeutic agents remains an urgent need. Pristimerin (PRIS), a natural bioactive component isolated from various plant species in the Celastraceae and Hippocrateaceae families, has been reported to exhibit outstanding antitumor effects in several types of cells. However, the underlying mechanisms involved remain poorly understood. Here, we reported the novel finding that PRIS significantly suppressed lung cancer growth in conditionally reprogrammed patient-derived lung adenocarcinoma cells (CRLCs). We demonstrated that PRIS inhibited the cell viabilities, migrative and invaded abilities, and capillary structure formation of CRLCs. Furthermore, our results clarified that PRIS induced mitochondrial dysfunction through reactive oxygen species (ROS) generation, activation of caspase-9, caspase-3, and caspase-4, and expression of endoplasmic reticulum (ER) stress-associated proteins. Inhibition of ER stress by 4-PBA (4-phenylbutyric acid, a specific ER stress inhibitor) or CHOP siRNA transfection ameliorated PRIS-induced loss of mitochondrial membrane potential and intrinsic apoptosis. The present study also provides mechanistic evidence that PRIS suppressed the EphB4/CDC42/N-WASP signaling pathway, which is required for mitochondrial-mediated intrinsic apoptosis, activation of ER stress, and stimulation of caspase-4 induced by PRIS, and consequently resulting in suppressed cell viability, migration, and angiogenesis in CRLCs. Taken together, by providing a mechanistic insight into the modulation of ER stress-induced cell death in CRLCs by PRIS, we suggest that PRIS has a strong potential of being a new antitumor therapeutic agent with applications in the fields of human lung adenocarcinoma. |
url |
http://dx.doi.org/10.1155/2020/7409853 |
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