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Original Article | Open Access

CD13 inhibition augments DR4-induced tumor cell death in a p-ERK1/2-independent manner

Jun Ni, Xiaofei Wang, Yue Shang, Yi Li, Shuzhen Chen ( )
Department of Cancer Research, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China
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Abstract

Objective

Death receptor 4 (DR4; TRAIL-R1) critically mediates extrinsic apoptosis cascades via binding to TNF-related apoptosis-inducing ligand (TRAIL). However, intrinsic and/or acquired resistance are observed in the clinical application of TRAIL. The aim of this study was to investigate the function and molecular mechanism of CD13 in the TRAIL/DR4 pathway against tumor cells, and provide a new strategy for improving therapeutic efficacy or overcoming TRAIL-resistance.

Methods

TRAIL protein was expressed as a secretory protein in a Pichia pastoris expression system and was isolated and purified by affinity chromatography. The cell viability and apoptosis were evaluated with MTT (thiazolyl blue tetrazolium bromide) assays and annexin V-FITC/PI staining with flow cytometry analysis, respectively. Western blot analysis was used to detect the levels of the indicated proteins in tumor cells. DR4 degradation or stability was examined with cycloheximide chase assays, and cell surface DR4 was assessed with flow cytometric analysis after staining with a FITC-conjugated antibody. The effects of cell migration were determined with Transwell and gelatin zymography assays. A xenograft nude mouse model was used to detect the anti-tumor effect in vivo, and the proliferation in tumor tissues was examined with immunohistochemical staining.

Results

CD13 inhibition potently sensitized tumor cells to TRAIL-induced killing, including proliferation inhibition, increased apoptosis, and migration suppression. In addition, the inhibition of CD13 elevated both total cellular expression and cell surface DR4 through stabilizing DR4 by suppressing its degradation. DR4 siRNA attenuated the enhanced anti-tumor effects of TRAIL plus CD13 inhibition. Interestingly, these phenomena were p-ERK1/2 independent, although p-ERK1/2 down-regulation was tightly correlated with the cooperation of TRAIL and CD13 inhibition. Moreover, a synergistic decrease in tumor growth was surprisingly achieved in the xenograft model by treatment of TRAIL with a CD13 inhibitor (**P < 0.01, CDI = 0.47).

Conclusions

CD13 inhibition cooperates with TRAIL in enhancing DR4-mediated cell death, through the up-regulation and stabilization of DR4 in a p-ERK1/2-independent manner. Thus CD13 inhibition has emerged as an effective strategy for TRAIL/DR4-based therapy.

Keywords

therapeutic targetsCD13 inhibitionDR4TRAILneoplasm

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Cancer Biology & Medicine
Volume 18 Issue 2,
May 2021
Pages 569-586
DOI: 10.20892/j.issn.2095-3941.2020.0196
Cite this article:
Ni J, Wang X, Shang Y, et al. CD13 inhibition augments DR4-induced tumor cell death in a p-ERK1/2-independent manner. Cancer Biology & Medicine, 2021, 18(2): 569-586. https://doi.org/10.20892/j.issn.2095-3941.2020.0196

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Received: 29 April 2020
Accepted: 18 September 2020
Published: 01 May 2021
©2021 Cancer Biology & Medicine.

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