Suppression of EGFR/PKC-δ/NF-κB Signaling Associated With Imipramine-Inhibited Progression of Non-Small Cell Lung Cancer.

Po-Fu Yueh,I-Tsang Chiang,Yuan-Hao Lee,Wei-Ting Chen,Fei-Ting Hsu,Keng-Li Lan,Cheng-Hsien Chen

doi:10.3389/fonc.2021.735183

Abstract

BackgroundAnti-depressants have been reported to own anti-tumor potential types of cancers; however, the role of imipramine in non-small cell lung cancer (NSCLC) has not been elucidated. Epidermal growth factor receptor (EGFR) was known to be one of the key regulators that control NSCLC progression. Whether EGFR would be the target of imipramine for suppressing tumor signaling transduction and results in anti-tumor potential is remaining unclear.MethodsWe used CL-1-5-F4 cells and animal models to identify the underlying mechanism and therapeutic efficacy of imipramine. Cytotoxicity, apoptosis, invasion/migration, DNA damage, nuclear translocation of NF-κB, activation of NF-κB, phosphorylation of EGFR/PKC-δ/NF-κB was assayed by MTT, flow cytometry, transwell, wound healing assay, comet assay, immunofluorescence staining, NF-κB reporter gene assay and Western blotting, respectively. Tumor growth was validated by CL-1-5-F4/NF-κB-luc2 bearing animal model.ResultsImipramine effectively induces apoptosis of NSCLC cells via both intrinsic and extrinsic apoptosis signaling. DNA damage was increased, while, invasion and migration potential of NSCLC cells was suppressed by imipramine. The phosphorylation of EGFR/PKC-δ/NF-κB and their downstream proteins were all decreased by imipramine. Similar tumor growth inhibition was found in imipramine with standard therapy erlotinib (EGFR inhibitor). Non-obvious body weight loss and liver pathology change were found in imipramine treatment mice.ConclusionImipramine-triggered anti-NSCLC effects in both in vitro and in vivo model are at least partially attributed to its suppression of EGFR/PKC-δ/NF-κB pathway.

Highlights

Anti-depressants have been reported to own anti-tumor potential types of cancers; the role of imipramine in non-small cell lung cancer (NSCLC) has not been elucidated
The Annexin-V+ cells were all increased along with dosage rising after imipramine treatment in three NSCLC cells (Figure 1C)
To further investigated whether imipramineinduced apoptosis was associated with caspase-dependent signaling activation, CL1-5-F4 cells were co-treated with imipramine with Z-VAD, a caspase family inhibitor, and tested by Annexin-V/PI staining

Summary

Introduction

Anti-depressants have been reported to own anti-tumor potential types of cancers; the role of imipramine in non-small cell lung cancer (NSCLC) has not been elucidated. Epidermal growth factor receptor (EGFR) was known to be one of the key regulators that control NSCLC progression. Indicated by cell and animal models, antidepressants as potential anti-cancer agents inhibit the growth of hepatocellular carcinoma, glioblastoma, and colorectal cancer through induction of apoptosis, inactivation of oncogenic kinases, and enhancement of anti-tumor immunity [6,7,8]. Imipramine, a TCA, can inhibit the progression of glioblastoma cells via potentiating dephosphorylation of extracellular regulated protein kinase (ERK) and apoptosis signaling [8]. Increased expression of anticancer cytokines interleukin-12 (IL12) and interferon-gamma (INFg) was found to be associated with mirtazapine, an atypical antidepressant that inhibited the growth of CRC cells [6]

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