CD44 inhibition attenuates EGFR signaling and enhances cisplatin sensitivity in human EGFR wild‑type non‑small‑cell lung cancer cells

Yin,Jianhua; Zhang,Hanyu; Wu,Xu; Zhang,Yuchen; Li,Jing; Shen,Jing; Zhao,Yueshui; Xiao,Zhangang; Lu,Lan; Huang,Chengliang; Zhang,Zhuo; Du,Fukuan; Wu,Yuanlin; Kaboli,Parham Jabbarzadeh; Cho,Chi Hin; Yuan,Dandan; Li,Mingxing

doi:10.3892/ijmm.2020.4562

CD44 inhibition attenuates EGFR signaling and enhances cisplatin sensitivity in human EGFR wild‑type non‑small‑cell lung cancer cells

Authors:
- Jianhua Yin
- Hanyu Zhang
- Xu Wu
- Yuchen Zhang
- Jing Li
- Jing Shen
- Yueshui Zhao
- Zhangang Xiao
- Lan Lu
- Chengliang Huang
- Zhuo Zhang
- Fukuan Du
- Yuanlin Wu
- Parham Jabbarzadeh Kaboli
- Chi Hin Cho
- Dandan Yuan
- Mingxing Li
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Affiliations: Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan 646000, P.R. China, Department of Anaesthesia and Intensive Care, The Chinese University of Hong Kong, Hong Kong, SAR 999077, P.R. China, Department of Oncology and Hematology, Hospital (T.C.M) Affiliated to Southwest Medical University, Luzhou, Sichuan 646000, P.R. China, Sichuan Industrial Institute of Antibiotics, Chengdu University, Chengdu, Sichuan 610000, P.R. China, Department of Respiratory and Critical Care Medicine II, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, P.R. China, Department of Internal Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong 250000, P.R. China
Published online on: April 1, 2020 https://doi.org/10.3892/ijmm.2020.4562
Pages: 1783-1792
Copyright: © Yin et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Cluster of differentiation 44 (CD44) as a transmembrane glycoprotein is found to be expressed in non‑small cell lung cancer (NSCLC), is significantly associated with NSLC progression, metastasis and drug resistance. This study aimed to explore whether CD44 inhibition improves the sensitivity of epidermal growth factor receptor (EGFR) wild‑type NSCLC cells to cisplatin and how it affects wild‑type EGFR in NSCLC cells. Small interfering RNA was used to knockdown CD44 expression in EGFR wild‑type NSCLC cell line H460. Results suggested that CD44 downregulation reduced cell growth, promoted G0/G1 cell cycle arrest and induced cell apoptosis in H460 cells and these effects were evidently enhanced when in combination with cisplatin. Deactivation of EGFR signaling pathway including EGFR phosphorylation and its downstream molecules, targets ERK, AKT1 and SRC which were also observed in CD44‑silenced H460 cells with or without EGF stimulation. Furthermore, the CD44 expression level was positively correlated with wild‑type EGFR level in human lung adenocarcinoma tissues and CD44 inhibition significantly accelerated the degradation of EGFR, indicating that enhanced sensitivity of H460 cells to cisplatin by downregulation of CD44 might be due to EGFR degradation. This study demonstrated that suppression of CD44 deactivated EGFR signals in NSCLC cells with wild‑type EGFR, thereby contributing to the inhibition of cell proliferation and the reinforcement of cisplatin sensitivity. It is suggested that downregulation of CD44 could be a novel potential therapeutic strategy for the treatment of EGFR wild‑type NSCLC.

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