Targeting PAK4 reverses cisplatin resistance in NSCLC by modulating ER stress

Chemoresistance poses a significant impediment to effective treatments for non-small-cell lung cancer (NSCLC). P21-activated kinase 4 (PAK4) has been implicated in NSCLC progression by invasion and migration. However, the involvement of PAK4 in cisplatin resistance is not clear. Here, we presented a...

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Published in:Cell death discovery 2024-01, Vol.10 (1), p.36-36, Article 36
Main Authors: Liu, Shixin, Yang, Pingshan, Wang, Lu, Zou, Xiaofang, Zhang, Dongdong, Chen, Wenyou, Hu, Chuang, Xiao, Duqing, Ren, Hongzheng, Zhang, Hao, Cai, Songwang
Format: Article
Language:English
Subjects:
631/67/1059/2326
631/67/1612/1350
Apoptosis
Biochemistry
Biomedical and Life Sciences
Cell Biology
Cell Cycle Analysis
Chemoresistance
Cisplatin
Endoplasmic reticulum
Life Sciences
Lung cancer
Non-small cell lung carcinoma
p21-activated kinase
Signal transduction
Small cell lung carcinoma
Stem Cells
Therapeutic targets
Tumor cells
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Summary:Chemoresistance poses a significant impediment to effective treatments for non-small-cell lung cancer (NSCLC). P21-activated kinase 4 (PAK4) has been implicated in NSCLC progression by invasion and migration. However, the involvement of PAK4 in cisplatin resistance is not clear. Here, we presented a comprehensive investigation into the involvement of PAK4 in cisplatin resistance within NSCLC. Our study revealed enhanced PAK4 expression in both cisplatin-resistant NSCLC tumors and cell lines. Notably, PAK4 silencing led to a remarkable enhancement in the chemosensitivity of cisplatin-resistant NSCLC cells. Cisplatin evoked endoplasmic reticulum stress in NSCLC. Furthermore, inhibition of PAK4 demonstrated the potential to sensitize resistant tumor cells through modulating endoplasmic reticulum stress. Mechanistically, we unveiled that the suppression of the MEK1-GRP78 signaling pathway results in the sensitization of NSCLC cells to cisplatin after PAK4 knockdown. Our findings establish PAK4 as a promising therapeutic target for addressing chemoresistance in NSCLC, potentially opening new avenues for enhancing treatment efficacy and patient outcomes.
ISSN:2058-7716
2058-7716
DOI:10.1038/s41420-024-01798-7