Overcoming multi-drug resistance in SCLC: a synergistic approach with venetoclax and hydroxychloroquine targeting the lncRNA LYPLAL1-DT/BCL2/BECN1 pathway.

Humans Small Cell Lung Carcinoma / drug therapy RNA, Long Noncoding / genetics Sulfonamides / pharmacology Animals Drug Resistance, Neoplasm / genetics Mice Lung Neoplasms / drug therapy Bridged Bicyclo Compounds, Heterocyclic / pharmacology Proto-Oncogene Proteins c-bcl-2 / metabolism Cell Line, Tumor Hydroxychloroquine / pharmacology Xenograft Model Antitumor Assays Beclin-1 / metabolism Drug Synergism Drug Resistance, Multiple / genetics Apoptosis / drug effects Gene Expression Regulation, Neoplastic / drug effects Autophagy / drug effects Cisplatin / pharmacology Cell Proliferation / drug effects Signal Transduction / drug effects Antineoplastic Combined Chemotherapy Protocols / pharmacology
Apoptosis Autophagy BCL2 BECN1 LYPLAL1-DT Multi-drug resistance Small cell lung cancer

Journal

Molecular cancer
ISSN: 1476-4598
Titre abrégé: Mol Cancer
Pays: England
ID NLM: 101147698

Informations de publication

Date de publication:
31 Oct 2024
Historique:
received: 26 04 2024
accepted: 04 10 2024
medline: 31 10 2024
pubmed: 31 10 2024
entrez: 31 10 2024
Statut: epublish

Résumé

Small cell lung cancer (SCLC) stands as one of the most lethal malignancies, characterized by a grim diagnosis and prognosis. The emergence of multi-drug resistance poses a significant hurdle to effective therapy. Although previous studies have implicated the long noncoding RNA LYPLAL1-DT in the tumorigenesis of SCLC, the precise role of the highly expressed LYPLAL1-DT in SCLC chemoresistance and the underlying mechanism remain inadequately understood. cDDP-, VP-16- and PTX-resistant SCLC cells lines were established. The viabilities of SCLC cells were assessed by CCK-8 assay in vitro and xenograft tumor formation assay in vivo. Apoptosis was evaluated by FACS, Western blot and JC-1 fluorescence staining, while autophagy was explored via autophagic flux detection under confocal microscopy and autophagic vacuole investigation under transmission electron microscopy (TEM). The functional role and mechanism of LYPLAL1-DT were further investigated by gain- and loss-of-function assays in vitro. Furthermore, the therapeutic efficacy of the combination of venetoclax and HCQ with cDDP, VP-16 or PTX was evaluated by cell line, cell-derived xenograft (CDX) and patient-derived xenograft (PDX) mice model. Our findings revealed that LYPLAL1-DT is upregulated in chemoresistant SCLC cell lines. Gain- and loss-of-function assays demonstrated that LYPLAL1-DT impairs sensitivity to cDDP, VP-16, or PTX both in vitro and in vivo. Overexpression of LYPLAL1-DT significantly enhanced autophagy and inhibited apoptosis in SCLC cells. Further analyses, including RIP and RNA pull-down assays, revealed that LYPLAL1-DT promotes the expression of BCL2 by sponging miR-204-5p and is implicated in the assembly of the autophagy-specific complex (BECN1/PtdIns3K complex). Combining venetoclax and HCQ with cDDP, VP-16, or PTX effectively mitigated chemoresistance in SCLC cells and suppressed tumor growth in CDX and PDX models without inducing obvious toxic effects. Our findings demonstrate that upregulation of LYPLAL1-DT sequesters apoptosis through the LYPLAL1-DT/miR-204-5p/BCL2 axis and promotes autophagy by facilitating the assembly of the BECN1/PtdIns3K complex, thereby mediating multi-drug resistance of SCLC. The triple combination of venetoclax, HCQ, in conjunction with cDDP, VP-16 or PTX overcomes refractory SCLC, shedding light on a potential therapeutic target for combating SCLC chemoresistance.

Sections du résumé

BACKGROUND BACKGROUND
Small cell lung cancer (SCLC) stands as one of the most lethal malignancies, characterized by a grim diagnosis and prognosis. The emergence of multi-drug resistance poses a significant hurdle to effective therapy. Although previous studies have implicated the long noncoding RNA LYPLAL1-DT in the tumorigenesis of SCLC, the precise role of the highly expressed LYPLAL1-DT in SCLC chemoresistance and the underlying mechanism remain inadequately understood.
METHODS METHODS
cDDP-, VP-16- and PTX-resistant SCLC cells lines were established. The viabilities of SCLC cells were assessed by CCK-8 assay in vitro and xenograft tumor formation assay in vivo. Apoptosis was evaluated by FACS, Western blot and JC-1 fluorescence staining, while autophagy was explored via autophagic flux detection under confocal microscopy and autophagic vacuole investigation under transmission electron microscopy (TEM). The functional role and mechanism of LYPLAL1-DT were further investigated by gain- and loss-of-function assays in vitro. Furthermore, the therapeutic efficacy of the combination of venetoclax and HCQ with cDDP, VP-16 or PTX was evaluated by cell line, cell-derived xenograft (CDX) and patient-derived xenograft (PDX) mice model.
RESULTS RESULTS
Our findings revealed that LYPLAL1-DT is upregulated in chemoresistant SCLC cell lines. Gain- and loss-of-function assays demonstrated that LYPLAL1-DT impairs sensitivity to cDDP, VP-16, or PTX both in vitro and in vivo. Overexpression of LYPLAL1-DT significantly enhanced autophagy and inhibited apoptosis in SCLC cells. Further analyses, including RIP and RNA pull-down assays, revealed that LYPLAL1-DT promotes the expression of BCL2 by sponging miR-204-5p and is implicated in the assembly of the autophagy-specific complex (BECN1/PtdIns3K complex). Combining venetoclax and HCQ with cDDP, VP-16, or PTX effectively mitigated chemoresistance in SCLC cells and suppressed tumor growth in CDX and PDX models without inducing obvious toxic effects.
CONCLUSIONS CONCLUSIONS
Our findings demonstrate that upregulation of LYPLAL1-DT sequesters apoptosis through the LYPLAL1-DT/miR-204-5p/BCL2 axis and promotes autophagy by facilitating the assembly of the BECN1/PtdIns3K complex, thereby mediating multi-drug resistance of SCLC. The triple combination of venetoclax, HCQ, in conjunction with cDDP, VP-16 or PTX overcomes refractory SCLC, shedding light on a potential therapeutic target for combating SCLC chemoresistance.

Identifiants

DOI: 10.1186/s12943-024-02145-1 PMID: 39478582
pubmed: 39478582
doi: 10.1186/s12943-024-02145-1
pii: 10.1186/s12943-024-02145-1
doi:

Substances chimiques

RNA, Long Noncoding 0
Sulfonamides 0
Bridged Bicyclo Compounds, Heterocyclic 0
venetoclax N54AIC43PW
Proto-Oncogene Proteins c-bcl-2 0
Hydroxychloroquine 4QWG6N8QKH
BCL2 protein, human 0
Beclin-1 0
Cisplatin Q20Q21Q62J

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

243

Subventions

Organisme : Beijing Municipal Public Welfare Development and Reform Pilot Project for Medical Research Institutes
ID : JYY2023-14

Informations de copyright

© 2024. The Author(s).

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Auteurs

Shuxin Li (S)

School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China.
Laboratory for Clinical Medicine, Capital Medical University, Beijing, 100069, China.
Beijing Key Laboratory of Cancer Invasion and Metastasis Research, Beijing, 100069, China.

Jianyi Lv (J)

School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China.
Laboratory for Clinical Medicine, Capital Medical University, Beijing, 100069, China.
Beijing Key Laboratory of Cancer Invasion and Metastasis Research, Beijing, 100069, China.

Zhihui Li (Z)

School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China.
Laboratory for Clinical Medicine, Capital Medical University, Beijing, 100069, China.
Beijing Key Laboratory of Cancer Invasion and Metastasis Research, Beijing, 100069, China.

Qiuyu Zhang (Q)

School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China.
Laboratory for Clinical Medicine, Capital Medical University, Beijing, 100069, China.
Beijing Key Laboratory of Cancer Invasion and Metastasis Research, Beijing, 100069, China.

Jing Lu (J)

School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China.
Laboratory for Clinical Medicine, Capital Medical University, Beijing, 100069, China.
Beijing Key Laboratory of Cancer Invasion and Metastasis Research, Beijing, 100069, China.

Xueyun Huo (X)

School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China.
Laboratory for Clinical Medicine, Capital Medical University, Beijing, 100069, China.
Beijing Key Laboratory of Cancer Invasion and Metastasis Research, Beijing, 100069, China.

Meng Guo (M)

School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China.
Laboratory for Clinical Medicine, Capital Medical University, Beijing, 100069, China.
Beijing Key Laboratory of Cancer Invasion and Metastasis Research, Beijing, 100069, China.

Xin Liu (X)

School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China.
Laboratory for Clinical Medicine, Capital Medical University, Beijing, 100069, China.
Beijing Key Laboratory of Cancer Invasion and Metastasis Research, Beijing, 100069, China.

Changlong Li (C)

School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China.
Laboratory for Clinical Medicine, Capital Medical University, Beijing, 100069, China.
Beijing Key Laboratory of Cancer Invasion and Metastasis Research, Beijing, 100069, China.

Jinghui Wang (J)

Department of Medical Oncology, Beijing Chest Hospital, Beijing Tuberculosis and Thoracic Tumor Research Institute, Capital Medical University, Beijing, 101149, China.

Hanping Shi (H)

Laboratory for Clinical Medicine, Capital Medical University, Beijing, 100069, China.
Department of Gastrointestinal Surgery/Clinical Nutrition, Capital Medical University Affiliated Beijing Shijitan Hospital, Beijing, 100038, China.

Li Deng (L)

Laboratory for Clinical Medicine, Capital Medical University, Beijing, 100069, China.
Department of Gastrointestinal Surgery/Clinical Nutrition, Capital Medical University Affiliated Beijing Shijitan Hospital, Beijing, 100038, China.

Zhenwen Chen (Z)

School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China.
Laboratory for Clinical Medicine, Capital Medical University, Beijing, 100069, China.
Beijing Key Laboratory of Cancer Invasion and Metastasis Research, Beijing, 100069, China.

Xiaoyan Du (X)

School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China. duduyan@ccmu.edu.cn.
Laboratory for Clinical Medicine, Capital Medical University, Beijing, 100069, China. duduyan@ccmu.edu.cn.
Beijing Key Laboratory of Cancer Invasion and Metastasis Research, Beijing, 100069, China. duduyan@ccmu.edu.cn.

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questionsmedicales.fr › Acides nucléiques, nucléotides et nucléosides › Acides nucléiques › ARN › ARN non traduit › ARN long non codant › Overcoming multi-drug resistance in SCLC: a...
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questionsmedicales.fr › Phénomènes physiologiques › Phénomènes pharmacologiques et toxicologiques › Phénomènes pharmacologiques › Résistance aux substances › Résistance aux médicaments antinéoplasiques › Overcoming multi-drug resistance in SCLC: a...
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questionsmedicales.fr › Maladies de l'appareil respiratoire › Tumeurs de l'appareil respiratoire › Tumeurs du poumon › Overcoming multi-drug resistance in SCLC: a...
questionsmedicales.fr › Composés hétérocycliques › Composés hétérocycliques, cycle ponté › Composés hétérocycliques bicycliques › Overcoming multi-drug resistance in SCLC: a...
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