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

被引：2

作者：

Li, Shuxin ^{[1
,2
,3
]}

Lv, Jianyi ^{[1
,2
,3
]}

Li, Zhihui ^{[1
,2
,3
]}

Zhang, Qiuyu ^{[1
,2
,3
]}

Lu, Jing ^{[1
,2
,3
]}

Huo, Xueyun ^{[1
,2
,3
]}

Guo, Meng ^{[1
,2
,3
]}

Liu, Xin ^{[1
,2
,3
]}

Li, Changlong ^{[1
,2
,3
]}

Wang, Jinghui ^{[4
]}

Shi, Hanping ^{[2
,5
]}

Deng, Li ^{[2
,5
]}

Chen, Zhenwen ^{[1
,2
,3
]}

Du, Xiaoyan ^{[1
,2
,3
]}

机构：

[1] Capital Med Univ, Sch Basic Med Sci, Beijing 100069, Peoples R China

[2] Capital Med Univ, Lab Clin Med, Beijing 100069, Peoples R China

[3] Beijing Key Lab Canc Invas & Metastasis Res, Beijing 100069, Peoples R China

[4] Capital Med Univ, Beijing Chest Hosp, Beijing TB & Thorac Tumor Res Inst, Dept Med Oncol, Beijing 101149, Peoples R China

[5] Capital Med Univ, Beijing Shijitan Hosp, Dept Gastrointestinal Surg Clin Nutr, Beijing 100038, Peoples R China

来源：

MOLECULAR CANCER | 2024年 / 23卷 / 01期

关键词：

LYPLAL1-DT; BCL2; BECN1; Apoptosis; Autophagy; Multi-drug resistance; Small cell lung cancer; AUTOPHAGY INHIBITION; CANCER CELLS; MECHANISMS; DEATH;

D O I：

10.1186/s12943-024-02145-1

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

BackgroundSmall 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.MethodscDDP-, 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.ResultsOur 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.ConclusionsOur 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.

引用

页数：20