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Targeting PAK4 reverses cisplatin resistance in NSCLC by modulating ER stress
Shixin Liu1,2, Pingshan Yang1, Lu Wang2
1Department of Thoracic Surgery, the First Affiliated Hospital of Jinan University, No.601 Huangpu Road West, Guangzhou, Guangdong, 510632, China.
Abstract:
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.
Insights
This study reveals that P21-activated kinase 4 (PAK4) drives chemoresistance in non-small-cell lung cancer (NSCLC). Inhibiting PAK4 enhances sensitivity to cisplatin by modulating endoplasmic reticulum stress and the MEK1-GRP78 pathway.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Chemoresistance is a major challenge in treating non-small-cell lung cancer (NSCLC).
- P21-activated kinase 4 (PAK4) is linked to NSCLC progression but its role in cisplatin resistance is unknown.
Purpose of the Study:
- To investigate the role of PAK4 in cisplatin resistance in NSCLC.
- To explore PAK4 as a potential therapeutic target for overcoming chemoresistance.
Main Methods:
- Examined PAK4 expression in cisplatin-resistant NSCLC tumors and cell lines.
- Assessed the effect of PAK4 silencing on chemosensitivity.
- Investigated the impact of PAK4 inhibition on endoplasmic reticulum stress and the MEK1-GRP78 pathway.
Main Results:
- PAK4 expression was elevated in resistant NSCLC.
- Silencing PAK4 significantly increased sensitivity to cisplatin.
- PAK4 inhibition sensitized resistant cells by modulating endoplasmic reticulum stress.
- Suppression of the MEK1-GRP78 pathway mediated sensitization after PAK4 knockdown.
Conclusions:
- PAK4 plays a crucial role in cisplatin resistance in NSCLC.
- Targeting PAK4 offers a potential strategy to enhance NSCLC treatment efficacy.
- Modulating endoplasmic reticulum stress and the MEK1-GRP78 pathway are key mechanisms.
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