2. Academic Validation
  3. Targeting PAK4 reverses cisplatin resistance in NSCLC by modulating ER stress

Targeting PAK4 reverses cisplatin resistance in NSCLC by modulating ER stress

  • Cell Death Discov. 2024 Jan 18;10(1):36. doi: 10.1038/s41420-024-01798-7.
Shixin Liu # 1 2,  Pingshan Yang # 1,  Lu Wang # 2,  Xiaofang Zou 3 4,  Dongdong Zhang 1,  Wenyou Chen 1,  Chuang Hu 1,  Duqing Xiao 1,  Hongzheng Ren 5 6,  Hao Zhang 7 8,  Songwang Cai 9
Affiliations

Affiliations

  • 1 Department of Thoracic Surgery, the First Affiliated Hospital of Jinan University, No.601 Huangpu Road West, Guangzhou, Guangdong, 510632, China.
  • 2 State Key Laboratory of Bioactive Molecules and Druggability Assessment, and Minister of Education Key Laboratory of Tumor Molecular Biology, Institute of Precision Cancer Medicine and Pathology, School of Medicine, Jinan University, Guangzhou, 510632, China.
  • 3 Department of Medical Oncology, Cancer Center, Meizhou People's Hospital (Huangtang Hospital), Meizhou Academy of Medical Sciences, Meizhou, China.
  • 4 Guangdong Provincial Key Laboratory of Precision Medicine and Clinical Translational Research of Hakka Population, Meizhou, China.
  • 5 Department of Pathology, Gongli Hospital, Naval Medical University, Shanghai, 200135, China. rhz01672@glhospital.com.
  • 6 Department of Pathology, Heping Hospital, Changzhi Medical College, Changzhi, 000465, China. rhz01672@glhospital.com.
  • 7 Department of Thoracic Surgery, the First Affiliated Hospital of Jinan University, No.601 Huangpu Road West, Guangzhou, Guangdong, 510632, China. haolabcancercenter@163.com.
  • 8 State Key Laboratory of Bioactive Molecules and Druggability Assessment, and Minister of Education Key Laboratory of Tumor Molecular Biology, Institute of Precision Cancer Medicine and Pathology, School of Medicine, Jinan University, Guangzhou; The Second Affiliated Hospital of Shantou University Medical College, Shantou, China. haolabcancercenter@163.com.
  • 9 Department of Thoracic Surgery, the First Affiliated Hospital of Jinan University, No.601 Huangpu Road West, Guangzhou, Guangdong, 510632, China. caisongwang@jnu.edu.cn.
  • # Contributed equally.
PMID: 38238316 DOI: 10.1038/s41420-024-01798-7
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.

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