PNU-74654 Suppresses TNFR1/IKB Alpha/p65 Signaling and Induces Cell Death in Testicular Cancer.

Wen-Jung Chen,Ya-Chuan Chang,Yu-Ze Luan,Wen-Wei Sung,Sung-Lang Chen,Tsung-Hsien Lee,Chia-Ying Yu

doi:10.3390/cimb44010016

Abstract

Testicular cancer (TC) is a rare malignancy worldwide and is the most common malignancy in males aged 15–44 years. The Wnt/β-catenin signaling pathway mediates numerous essential cellular functions and has potentially important effects on tumorigenesis and cancer progression. The search for drugs to inhibit this pathway has identified a small molecule, PNU-74654, as an inhibitor of the β-catenin/TCF4 interaction. We evaluated the therapeutic role of PNU-74654 in two TC cell lines, NCCIT and NTERA2, by measuring cell viability, cell cycle transition and cell death. Potential pathways were evaluated by protein arrays and Western blots. PNU-74654 decreased cell viability and induced apoptosis of TC cells, with significant increases in the sub G1, Hoechst-stained, Annexin V-PI-positive rates. PNU-74654 treatment of both TC cell lines inhibited the TNFR1/IKB alpha/p65 pathway and the execution phase of apoptosis. Our findings demonstrate that PNU-74654 can induce apoptosis in TC cells through mechanisms involving the execution phase of apoptosis and inhibition of TNFR1/IKB alpha/p65 signaling. Therefore, small molecules such as PNU-74654 may identify potential new treatment strategies for TC.

Highlights

Testicular cancer is a rare malignancy in males worldwide and accounts for about 1%of newly diagnosed male cancers every year [1]
Cells after 24 h treatment with 50 and 200 μM PNU-74654 compared with the untreated control groups (NCCIT: control vs. 50 μM and 200 μM, p value = 0.002 and 0.001; NTERA2: control vs. 50 μM and 200 μM, p value = 0.564 and 0.002)
The findings of the current study confirmed that PNU-74654 can exert a cytotoxic effect on Testicular cancer (TC) cells by inducing apoptosis

Summary

Introduction

Testicular cancer is a rare malignancy in males worldwide and accounts for about 1%. Of newly diagnosed male cancers every year [1]. It shows a specific age distribution, as it is most commonly encountered in males aged 15–44 years [2]. The incidence of this male cancer has been increasing in many developed countries in the last decades [3]. The overall five-year survival is as high as 97% with effective treatment [4]. The development of effective treatments depends on knowledge of the mechanisms that cause testicular tissues to become cancerous

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