Cytochalasin H enhances sensitivity to gefitinib in non-small-cell lung cancer cells through inhibiting EGFR activation and PD-L1 expression

• Published in: Scientific reports Vol. 14; no. 1; pp. 25276 - 13
• Main Authors: Zhang, Guihong, Liu, Jiao, Li, Sanzhong, Wang, Tianyu, Chen, Li, Li, Huan, Ding, Qingkai, Li, Xiangyong, Zhu, Shaoping, Tang, Xudong
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 25.10.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 631/154/436; 631/67/1059; 631/67/1612; 631/67/2195; 692/4028/67; A549 Cells; Animal models; Animal research; Animals; Antineoplastic Agents - pharmacology; Apoptosis; B7-H1 Antigen - genetics; B7-H1 Antigen - metabolism; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - metabolism; Carcinoma, Non-Small-Cell Lung - pathology; Cell activation; Cell death; Cell Line, Tumor; Cell proliferation; Cell Proliferation - drug effects; Cytochalasin H; Cytochalasins - pharmacology; Drug Resistance, Neoplasm - drug effects; EGFR; Endophytes; Epidermal growth factor receptors; ErbB Receptors - metabolism; Gefitinib; Gefitinib - pharmacology; Humanities and Social Sciences; Humans; Inhibitor drugs; JAK3-STAT; Lung cancer; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Mice; Mice, Nude; multidisciplinary; Mutation; Non-small cell lung carcinoma; NSCLC; PD-L1; PD-L1 protein; Science; Science (multidisciplinary); Signal transduction; Small cell lung carcinoma; Targeted cancer therapy; Tyrosine kinase inhibitors; Xenograft Model Antitumor Assays; PD-L1; JAK3-STAT; NSCLC; Gefitinib; Cytochalasin H; EGFR
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-024-76060-2

In our previous study, we have isolated cytochalasin H (CyH) from endophytic fungus derived from mangrove plant and found that CyH inhibited the proliferation of non-small cell lung cancer (NSCLC) cells. Recently, epidermal growth factor receptor (EGFR) activation and programmed cell death 1 ligand (PD-L1) expression have been demonstrated to mediate NSCLC resistance to gefitinib, first-generation EGFR tyrosine kinase inhibitor (EGFR-TKI). Here, we further investigated the effect of CyH on EGFR activation, PD-L1 expression, and gefitinib sensitivity in NSCLC cell lines, A549 (wild-type EGFR), HCC827 (EGFR mutation), and NCI-H1975 (dual EGFR mutations and acquired gefitinib resistance) and animal model. Our results showed that CyH significantly inhibited EGFR activation and PD-L1 expression in NSCLC cells. Additionally, CyH dramatically promoted the inhibitory effect of gefitinib on the proliferation of A549 and HCC827 cells, and enhanced the sensitivity to gefitinib in NCI-H1975 cells. Moreover, CyH increased the inhibitory effect of gefitinib on EGFR activation and PD-L1 expression in HCC827 and NCI-H1975 cells. Animal experiments further demonstrated that CyH significantly promoted the inhibitory effect of gefitinib on the growth of NSCLC and the expression of Ki-67, p-EGFR, and PD-L1 in NCI-H1975 NSCLC xenograft tumors of nude mice. Furthermore, CyH inhibited the activation of JAK3/STAT signaling pathway. Taken together, our findings suggest that CyH promotes the sensitivity to gefitinib in NSCLC cells through the inhibition of EGFR activation and PD-L1 expression.