Near‐Death Cells Cause Chemotherapy‐Induced Metastasis via ATF4‐Mediated NF‐κB Signaling Activation
Abstract Cytotoxic chemotherapy is a primary treatment modality for many patients with advanced cancer. Increasing preclinical and clinical observations indicate that chemotherapy can exacerbate tumor metastasis. However, the underlying mechanism remains unclear. Here, it is attempted to identify th...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2023-04-01
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| Series: | Advanced Science |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/advs.202205835 |
| _version_ | 1797851974257868800 |
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| author | Chenchen Zhu Pei Liu Chuan‐Yuan Li Yuli Zhang Jiang Yin Linlin Hou Guopei Zheng Xinjian Liu |
| author_facet | Chenchen Zhu Pei Liu Chuan‐Yuan Li Yuli Zhang Jiang Yin Linlin Hou Guopei Zheng Xinjian Liu |
| author_sort | Chenchen Zhu |
| collection | DOAJ |
| description | Abstract Cytotoxic chemotherapy is a primary treatment modality for many patients with advanced cancer. Increasing preclinical and clinical observations indicate that chemotherapy can exacerbate tumor metastasis. However, the underlying mechanism remains unclear. Here, it is attempted to identify the mechanisms underlying chemotherapy‐induced cancer recurrence and metastasis. It is revealed that a small subpopulation of “near‐death cells” (NDCs) with compromised plasma membranes can reverse the death process to enhance survival and repopulation after exposure to lethal doses of cytotoxins. Moreover, these NDCs acquire enhanced tumorigenic and metastatic capabilities, but maintain chemosensitivity in multiple models. Mechanistically, cytotoxin exposure induces activating transcription factor 4 (ATF4)‐dependent nonclassical NF‐κB signaling activation; ultimately, this results in nuclear translocation of p52 and RelB in NDCs. Deletion of ATF4 in parental cancer cells significantly reduces colony formation and metastasis of NDCs, whereas overexpression of ATF4 activates the nonclassical NF‐κB signaling pathway to promote chemotherapy‐induced metastasis of NDCs. Overall, these results provide novel mechanistic insights into the chemotherapy‐induced metastasis and indicate the pivotal role of NDCs in mediating tumor relapse after cytotoxic therapy. This study also suggests that targeting ATF4 may be an effective approach in improving the efficacy of chemotherapy. |
| first_indexed | 2024-04-09T19:26:31Z |
| format | Article |
| id | doaj.art-4f088ce3ad7f4763927fb8cc71af8725 |
| institution | Directory Open Access Journal |
| issn | 2198-3844 |
| language | English |
| last_indexed | 2024-04-09T19:26:31Z |
| publishDate | 2023-04-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj.art-4f088ce3ad7f4763927fb8cc71af87252023-04-05T08:09:48ZengWileyAdvanced Science2198-38442023-04-011010n/an/a10.1002/advs.202205835Near‐Death Cells Cause Chemotherapy‐Induced Metastasis via ATF4‐Mediated NF‐κB Signaling ActivationChenchen Zhu0Pei Liu1Chuan‐Yuan Li2Yuli Zhang3Jiang Yin4Linlin Hou5Guopei Zheng6Xinjian Liu7Department of Biochemistry School of Medicine Shenzhen Campus of Sun Yat‐sen University Shenzhen Guangdong 510275 ChinaDepartment of Biochemistry School of Medicine Shenzhen Campus of Sun Yat‐sen University Shenzhen Guangdong 510275 ChinaDepartment of Dermatology Duke University Medical Center Durham NC 27710 USADepartment of Biochemistry School of Medicine Shenzhen Campus of Sun Yat‐sen University Shenzhen Guangdong 510275 ChinaCancer Research Institute and Cancer Hospital Guangzhou Medical University Guangzhou Guangdong 510180 ChinaDepartment of Biochemistry School of Medicine Shenzhen Campus of Sun Yat‐sen University Shenzhen Guangdong 510275 ChinaCancer Research Institute and Cancer Hospital Guangzhou Medical University Guangzhou Guangdong 510180 ChinaDepartment of Biochemistry School of Medicine Shenzhen Campus of Sun Yat‐sen University Shenzhen Guangdong 510275 ChinaAbstract Cytotoxic chemotherapy is a primary treatment modality for many patients with advanced cancer. Increasing preclinical and clinical observations indicate that chemotherapy can exacerbate tumor metastasis. However, the underlying mechanism remains unclear. Here, it is attempted to identify the mechanisms underlying chemotherapy‐induced cancer recurrence and metastasis. It is revealed that a small subpopulation of “near‐death cells” (NDCs) with compromised plasma membranes can reverse the death process to enhance survival and repopulation after exposure to lethal doses of cytotoxins. Moreover, these NDCs acquire enhanced tumorigenic and metastatic capabilities, but maintain chemosensitivity in multiple models. Mechanistically, cytotoxin exposure induces activating transcription factor 4 (ATF4)‐dependent nonclassical NF‐κB signaling activation; ultimately, this results in nuclear translocation of p52 and RelB in NDCs. Deletion of ATF4 in parental cancer cells significantly reduces colony formation and metastasis of NDCs, whereas overexpression of ATF4 activates the nonclassical NF‐κB signaling pathway to promote chemotherapy‐induced metastasis of NDCs. Overall, these results provide novel mechanistic insights into the chemotherapy‐induced metastasis and indicate the pivotal role of NDCs in mediating tumor relapse after cytotoxic therapy. This study also suggests that targeting ATF4 may be an effective approach in improving the efficacy of chemotherapy.https://doi.org/10.1002/advs.202205835ATF4chemotherapymetastasisnear‐death cellsnonclassical NF‐κB pathway |
| spellingShingle | Chenchen Zhu Pei Liu Chuan‐Yuan Li Yuli Zhang Jiang Yin Linlin Hou Guopei Zheng Xinjian Liu Near‐Death Cells Cause Chemotherapy‐Induced Metastasis via ATF4‐Mediated NF‐κB Signaling Activation Advanced Science ATF4 chemotherapy metastasis near‐death cells nonclassical NF‐κB pathway |
| title | Near‐Death Cells Cause Chemotherapy‐Induced Metastasis via ATF4‐Mediated NF‐κB Signaling Activation |
| title_full | Near‐Death Cells Cause Chemotherapy‐Induced Metastasis via ATF4‐Mediated NF‐κB Signaling Activation |
| title_fullStr | Near‐Death Cells Cause Chemotherapy‐Induced Metastasis via ATF4‐Mediated NF‐κB Signaling Activation |
| title_full_unstemmed | Near‐Death Cells Cause Chemotherapy‐Induced Metastasis via ATF4‐Mediated NF‐κB Signaling Activation |
| title_short | Near‐Death Cells Cause Chemotherapy‐Induced Metastasis via ATF4‐Mediated NF‐κB Signaling Activation |
| title_sort | near death cells cause chemotherapy induced metastasis via atf4 mediated nf κb signaling activation |
| topic | ATF4 chemotherapy metastasis near‐death cells nonclassical NF‐κB pathway |
| url | https://doi.org/10.1002/advs.202205835 |
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