Deferoxamine Counteracts Cisplatin Resistance in A549 Lung Adenocarcinoma Cells by Increasing Vulnerability to Glutamine Deprivation-Induced Cell Death
Glutamine, like glucose, is a major nutrient consumed by cancer cells, yet these cells undergo glutamine starvation in the cores of tumors, forcing them to evolve adaptive metabolic responses. Pharmacologically targeting glutamine metabolism or withdrawal has been exploited for therapeutic purposes,...
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Frontiers Media S.A.
2022-01-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2021.794735/full |
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| author | Wen-Jun Liu Wen-Jun Liu Peng-yu Pan Ye Sun Jian-bo Wang Huan Zhou Xin Xie Zhi-yuan Duan Han-yu Dong Wen-na Chen Li-de Zhang Chun Wang |
| author_facet | Wen-Jun Liu Wen-Jun Liu Peng-yu Pan Ye Sun Jian-bo Wang Huan Zhou Xin Xie Zhi-yuan Duan Han-yu Dong Wen-na Chen Li-de Zhang Chun Wang |
| author_sort | Wen-Jun Liu |
| collection | DOAJ |
| description | Glutamine, like glucose, is a major nutrient consumed by cancer cells, yet these cells undergo glutamine starvation in the cores of tumors, forcing them to evolve adaptive metabolic responses. Pharmacologically targeting glutamine metabolism or withdrawal has been exploited for therapeutic purposes, but does not always induce cancer cell death. The mechanism by which cancer cells adapt to resist glutamine starvation in cisplatin-resistant non-small-cell lung cancer (NSCLC) also remains uncertain. Here, we report the potential metabolic vulnerabilities of A549/DDP (drug-resistant human lung adenocarcinoma cell lines) cells, which were more easily killed by the iron chelator deferoxamine (DFO) during glutamine deprivation than their parental cisplatin-sensitive A549 cells. We demonstrate that phenotype resistance to cisplatin is accompanied by adaptive responses during glutamine deprivation partly via higher levels of autophagic activity and apoptosis resistance characteristics. Moreover, this adaptation could be explained by sustained glucose instead of glutamine-dominant complex II-dependent oxidative phosphorylation (OXPHOS). Further investigation revealed that cisplatin-resistant cells sustain OXPHOS partly via iron metabolism reprogramming during glutamine deprivation. This reprogramming might be responsible for mitochondrial iron-sulfur [Fe-S] cluster biogenesis, which has become an “Achilles’ heel,” rendering cancer cells vulnerable to DFO-induced autophagic cell death and apoptosis through c-Jun N-terminal kinase (JNK) signaling. Finally, in vivo studies using xenograft mouse models also confirmed the growth-slowing effect of DFO. In summary, we have elucidated the adaptive responses of cisplatin-resistant NSCLC cells, which balanced stability and plasticity to overcome metabolic reprogramming and permitted them to survive under stress induced by chemotherapy or glutamine starvation. In addition, for the first time, we show that suppressing the growth of cisplatin-resistant NSCLC cells via iron chelator-induced autophagic cell death and apoptosis was possible with DFO treatment. These findings provide a solid basis for targeting mitochondria iron metabolism in cisplatin-resistant NSCLC for therapeutic purposes, and it is plausible to consider that DFO facilitates in the improvement of treatment responses in cisplatin-resistant NSCLC patients. |
| first_indexed | 2024-04-11T15:37:02Z |
| format | Article |
| id | doaj.art-965a627964034217aa5dbc4f658d94de |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-04-11T15:37:02Z |
| publishDate | 2022-01-01 |
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| series | Frontiers in Oncology |
| spelling | doaj.art-965a627964034217aa5dbc4f658d94de2022-12-22T04:15:56ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2022-01-011110.3389/fonc.2021.794735794735Deferoxamine Counteracts Cisplatin Resistance in A549 Lung Adenocarcinoma Cells by Increasing Vulnerability to Glutamine Deprivation-Induced Cell DeathWen-Jun Liu0Wen-Jun Liu1Peng-yu Pan2Ye Sun3Jian-bo Wang4Huan Zhou5Xin Xie6Zhi-yuan Duan7Han-yu Dong8Wen-na Chen9Li-de Zhang10Chun Wang11Teaching and Experimental Center, Liaoning University of Traditional Chinese Medicine, Shenyang, ChinaDepartment of Cell Biology, College of Integrated Chinese and Western Medical, Liaoning University of Traditional Chinese Medicine, Shenyang, ChinaDepartment of Cell Biology, College of Integrated Chinese and Western Medical, Liaoning University of Traditional Chinese Medicine, Shenyang, ChinaKey Laboratory of Environmental Pollution and Microecology of Liaoning Province, Shenyang Medical College, Shenyang, ChinaKey Laboratory of Ministry of Education for Traditional Chinese Medicine (TCM) Viscera-State Theory and Applications, Liaoning University of Traditional Chinese Medicine, Shenyang, ChinaDepartment of Cell Biology, College of Integrated Chinese and Western Medical, Liaoning University of Traditional Chinese Medicine, Shenyang, ChinaTeaching and Experimental Center, Liaoning University of Traditional Chinese Medicine, Shenyang, ChinaTeaching and Experimental Center, Liaoning University of Traditional Chinese Medicine, Shenyang, ChinaDepartment of Cell Biology, College of Integrated Chinese and Western Medical, Liaoning University of Traditional Chinese Medicine, Shenyang, ChinaKey Laboratory of Ministry of Education for Traditional Chinese Medicine (TCM) Viscera-State Theory and Applications, Liaoning University of Traditional Chinese Medicine, Shenyang, ChinaDepartment of Cell Biology, College of Integrated Chinese and Western Medical, Liaoning University of Traditional Chinese Medicine, Shenyang, ChinaDepartment of Cell Biology, College of Integrated Chinese and Western Medical, Liaoning University of Traditional Chinese Medicine, Shenyang, ChinaGlutamine, like glucose, is a major nutrient consumed by cancer cells, yet these cells undergo glutamine starvation in the cores of tumors, forcing them to evolve adaptive metabolic responses. Pharmacologically targeting glutamine metabolism or withdrawal has been exploited for therapeutic purposes, but does not always induce cancer cell death. The mechanism by which cancer cells adapt to resist glutamine starvation in cisplatin-resistant non-small-cell lung cancer (NSCLC) also remains uncertain. Here, we report the potential metabolic vulnerabilities of A549/DDP (drug-resistant human lung adenocarcinoma cell lines) cells, which were more easily killed by the iron chelator deferoxamine (DFO) during glutamine deprivation than their parental cisplatin-sensitive A549 cells. We demonstrate that phenotype resistance to cisplatin is accompanied by adaptive responses during glutamine deprivation partly via higher levels of autophagic activity and apoptosis resistance characteristics. Moreover, this adaptation could be explained by sustained glucose instead of glutamine-dominant complex II-dependent oxidative phosphorylation (OXPHOS). Further investigation revealed that cisplatin-resistant cells sustain OXPHOS partly via iron metabolism reprogramming during glutamine deprivation. This reprogramming might be responsible for mitochondrial iron-sulfur [Fe-S] cluster biogenesis, which has become an “Achilles’ heel,” rendering cancer cells vulnerable to DFO-induced autophagic cell death and apoptosis through c-Jun N-terminal kinase (JNK) signaling. Finally, in vivo studies using xenograft mouse models also confirmed the growth-slowing effect of DFO. In summary, we have elucidated the adaptive responses of cisplatin-resistant NSCLC cells, which balanced stability and plasticity to overcome metabolic reprogramming and permitted them to survive under stress induced by chemotherapy or glutamine starvation. In addition, for the first time, we show that suppressing the growth of cisplatin-resistant NSCLC cells via iron chelator-induced autophagic cell death and apoptosis was possible with DFO treatment. These findings provide a solid basis for targeting mitochondria iron metabolism in cisplatin-resistant NSCLC for therapeutic purposes, and it is plausible to consider that DFO facilitates in the improvement of treatment responses in cisplatin-resistant NSCLC patients.https://www.frontiersin.org/articles/10.3389/fonc.2021.794735/fullNSCLCcisplatin resistanceglutamine deprivationmetabolic reprogrammingdeferoxaminecell death |
| spellingShingle | Wen-Jun Liu Wen-Jun Liu Peng-yu Pan Ye Sun Jian-bo Wang Huan Zhou Xin Xie Zhi-yuan Duan Han-yu Dong Wen-na Chen Li-de Zhang Chun Wang Deferoxamine Counteracts Cisplatin Resistance in A549 Lung Adenocarcinoma Cells by Increasing Vulnerability to Glutamine Deprivation-Induced Cell Death Frontiers in Oncology NSCLC cisplatin resistance glutamine deprivation metabolic reprogramming deferoxamine cell death |
| title | Deferoxamine Counteracts Cisplatin Resistance in A549 Lung Adenocarcinoma Cells by Increasing Vulnerability to Glutamine Deprivation-Induced Cell Death |
| title_full | Deferoxamine Counteracts Cisplatin Resistance in A549 Lung Adenocarcinoma Cells by Increasing Vulnerability to Glutamine Deprivation-Induced Cell Death |
| title_fullStr | Deferoxamine Counteracts Cisplatin Resistance in A549 Lung Adenocarcinoma Cells by Increasing Vulnerability to Glutamine Deprivation-Induced Cell Death |
| title_full_unstemmed | Deferoxamine Counteracts Cisplatin Resistance in A549 Lung Adenocarcinoma Cells by Increasing Vulnerability to Glutamine Deprivation-Induced Cell Death |
| title_short | Deferoxamine Counteracts Cisplatin Resistance in A549 Lung Adenocarcinoma Cells by Increasing Vulnerability to Glutamine Deprivation-Induced Cell Death |
| title_sort | deferoxamine counteracts cisplatin resistance in a549 lung adenocarcinoma cells by increasing vulnerability to glutamine deprivation induced cell death |
| topic | NSCLC cisplatin resistance glutamine deprivation metabolic reprogramming deferoxamine cell death |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2021.794735/full |
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