Suppression of the LKB1-AMPK-SLC7A11-GSH signaling pathway sensitizes NSCLC to albumin-bound paclitaxel via oxidative stress
Albumin-bound paclitaxel (nab-PTX) is an important chemotherapeutic drug used for the treatment of advanced and metastatic non-small cell lung cancer (NSCLC). One critical issue in its clinical application is the development of resistance; thus, a deeper understanding of the mechanisms underlying th...
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| Format: | Article |
| Language: | English |
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Elsevier
2025-04-01
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| Series: | Redox Biology |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2213231725000801 |
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| author | Dade Rong Liangliang Gao Yiguan Chen Xiang-Zheng Gao Mingzhu Tang Haimei Tang Yuan Gao Guang Lu Zhi-Qiang Ling Han-Ming Shen |
| author_facet | Dade Rong Liangliang Gao Yiguan Chen Xiang-Zheng Gao Mingzhu Tang Haimei Tang Yuan Gao Guang Lu Zhi-Qiang Ling Han-Ming Shen |
| author_sort | Dade Rong |
| collection | DOAJ |
| description | Albumin-bound paclitaxel (nab-PTX) is an important chemotherapeutic drug used for the treatment of advanced and metastatic non-small cell lung cancer (NSCLC). One critical issue in its clinical application is the development of resistance; thus, a deeper understanding of the mechanisms underlying the primary resistance to nab-PTX is expected to help to develop effective therapeutic strategies to overcome resistance. In this study, we made an unexpected discovery that NSCLC with wild-type (WT) Liver kinase B1 (LKB1), an important tumor suppressor and upstream kinase of AMP-activated protein kinase (AMPK), is more resistant to nab-PTX than NSCLC with mutant LKB1. Mechanistically, LKB1 status does not alter the intracellular concentration of nab-PTX or affect its canonical pharmacological action in promoting microtubule polymerization. Instead, we found that LKB1 mediates AMPK activation, leading to increased expression of SLC7A11, a key amino acid transporter and intracellular level of glutathione (GSH), which then attenuates the production of reactive oxygen species (ROS) and apoptotic cell death induced by nab-PTX. On the other hand, genetic or pharmacological inhibition of AMPK in LKB1-WT NSCLC reduces the expression of SLC7A11 and intracellular GSH, increases ROS level, and eventually promotes the apoptotic cell death induced by nab-PTX in vitro. Consistently, the combination of nab-PTX with an AMPK inhibitor exhibits a greater therapeutic efficacy in LKB1-WT NSCLC using xenograft models in vivo. Taken together, our data reveal a novel role of LKB1-AMPK-SLC7A11-GSH signaling pathway in the primary resistance to nab-PTX, and provide a therapeutic strategy for the treatment of LKB1-WT NSCLC by targeting the LKB1-AMPK-SLC7A11-GSH pathway. |
| format | Article |
| id | doaj-art-de563cfe38c74712a539f1a44706c7fc |
| institution | OA Journals |
| issn | 2213-2317 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Redox Biology |
| spelling | doaj-art-de563cfe38c74712a539f1a44706c7fc2025-08-20T02:07:17ZengElsevierRedox Biology2213-23172025-04-018110356710.1016/j.redox.2025.103567Suppression of the LKB1-AMPK-SLC7A11-GSH signaling pathway sensitizes NSCLC to albumin-bound paclitaxel via oxidative stressDade Rong0Liangliang Gao1Yiguan Chen2Xiang-Zheng Gao3Mingzhu Tang4Haimei Tang5Yuan Gao6Guang Lu7Zhi-Qiang Ling8Han-Ming Shen9Faculty of Health Sciences, Ministry of Education Frontiers Science Center for Precision Oncology, University of Macau, Macau, ChinaFaculty of Health Sciences, Ministry of Education Frontiers Science Center for Precision Oncology, University of Macau, Macau, ChinaFaculty of Health Sciences, Ministry of Education Frontiers Science Center for Precision Oncology, University of Macau, Macau, ChinaFaculty of Health Sciences, Ministry of Education Frontiers Science Center for Precision Oncology, University of Macau, Macau, ChinaFaculty of Health Sciences, Ministry of Education Frontiers Science Center for Precision Oncology, University of Macau, Macau, ChinaFaculty of Health Sciences, Ministry of Education Frontiers Science Center for Precision Oncology, University of Macau, Macau, China; Department of Immunology, Shenzhen University School of Medicine, Shenzhen, ChinaFaculty of Health Sciences, Ministry of Education Frontiers Science Center for Precision Oncology, University of Macau, Macau, ChinaDepartment of Physiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, ChinaExperimental Research Centre, The Cancer Hospital of the University of Chinese Academy of Sciences, Zhejiang Cancer Hospital, Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, Zhejiang, 310022, ChinaFaculty of Health Sciences, Ministry of Education Frontiers Science Center for Precision Oncology, University of Macau, Macau, China; Corresponding author.Albumin-bound paclitaxel (nab-PTX) is an important chemotherapeutic drug used for the treatment of advanced and metastatic non-small cell lung cancer (NSCLC). One critical issue in its clinical application is the development of resistance; thus, a deeper understanding of the mechanisms underlying the primary resistance to nab-PTX is expected to help to develop effective therapeutic strategies to overcome resistance. In this study, we made an unexpected discovery that NSCLC with wild-type (WT) Liver kinase B1 (LKB1), an important tumor suppressor and upstream kinase of AMP-activated protein kinase (AMPK), is more resistant to nab-PTX than NSCLC with mutant LKB1. Mechanistically, LKB1 status does not alter the intracellular concentration of nab-PTX or affect its canonical pharmacological action in promoting microtubule polymerization. Instead, we found that LKB1 mediates AMPK activation, leading to increased expression of SLC7A11, a key amino acid transporter and intracellular level of glutathione (GSH), which then attenuates the production of reactive oxygen species (ROS) and apoptotic cell death induced by nab-PTX. On the other hand, genetic or pharmacological inhibition of AMPK in LKB1-WT NSCLC reduces the expression of SLC7A11 and intracellular GSH, increases ROS level, and eventually promotes the apoptotic cell death induced by nab-PTX in vitro. Consistently, the combination of nab-PTX with an AMPK inhibitor exhibits a greater therapeutic efficacy in LKB1-WT NSCLC using xenograft models in vivo. Taken together, our data reveal a novel role of LKB1-AMPK-SLC7A11-GSH signaling pathway in the primary resistance to nab-PTX, and provide a therapeutic strategy for the treatment of LKB1-WT NSCLC by targeting the LKB1-AMPK-SLC7A11-GSH pathway.http://www.sciencedirect.com/science/article/pii/S2213231725000801Albumin-bound paclitaxelLKB1Non-small lung cancerAMPKSLC7A11ROS |
| spellingShingle | Dade Rong Liangliang Gao Yiguan Chen Xiang-Zheng Gao Mingzhu Tang Haimei Tang Yuan Gao Guang Lu Zhi-Qiang Ling Han-Ming Shen Suppression of the LKB1-AMPK-SLC7A11-GSH signaling pathway sensitizes NSCLC to albumin-bound paclitaxel via oxidative stress Redox Biology Albumin-bound paclitaxel LKB1 Non-small lung cancer AMPK SLC7A11 ROS |
| title | Suppression of the LKB1-AMPK-SLC7A11-GSH signaling pathway sensitizes NSCLC to albumin-bound paclitaxel via oxidative stress |
| title_full | Suppression of the LKB1-AMPK-SLC7A11-GSH signaling pathway sensitizes NSCLC to albumin-bound paclitaxel via oxidative stress |
| title_fullStr | Suppression of the LKB1-AMPK-SLC7A11-GSH signaling pathway sensitizes NSCLC to albumin-bound paclitaxel via oxidative stress |
| title_full_unstemmed | Suppression of the LKB1-AMPK-SLC7A11-GSH signaling pathway sensitizes NSCLC to albumin-bound paclitaxel via oxidative stress |
| title_short | Suppression of the LKB1-AMPK-SLC7A11-GSH signaling pathway sensitizes NSCLC to albumin-bound paclitaxel via oxidative stress |
| title_sort | suppression of the lkb1 ampk slc7a11 gsh signaling pathway sensitizes nsclc to albumin bound paclitaxel via oxidative stress |
| topic | Albumin-bound paclitaxel LKB1 Non-small lung cancer AMPK SLC7A11 ROS |
| url | http://www.sciencedirect.com/science/article/pii/S2213231725000801 |
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