Targeting a novel cancer-driving protein (LAPTM4B-35) by a small molecule (ETS) to inhibit cancer growth and metastasis.

Maojin Li,Rouli Zhou,Yi Shan,Lin Wang,Gang Liu,Li Li

doi:10.18632/oncotarget.11325

Abstract

Our previous studies demonstrated that LAPTM4B-35 is overexpressed in a variety of solid cancers including hepatocellular carcinoma (HCC), and is an independent factor for prognosis. LAPTM4B-35 overexpression causes carcinogenesis and enhances cancer growth, metastasis and multidrug resistance, and thus may be a candidate for therapeutic targeting. The present study shows ethylglyoxal bisthiosemicarbazon (ETS) has effective anticancer activity through LAPTM4B-35 targeting. Bel-7402 and HepG2 cell lines from human HCC were used as cell models in which LAPTM4B-35 is highly expressed, and a human fetal liver cell line was used as a control. The results showed ETS has a specific and pronounced lethal effect on HCC cells, but not on fetal liver cells in culture. ETS also attenuated growth and metastasis of human HCC xenograft in nude mice, and extended the life span of mice with HCC. ETS induced HCC cell apoptosis, and upregulated a large number of proapoptotic genes and downregulated antiapoptotic genes. When endogenous overexpression of LAPTM4B-35 was knocked down with RNAi, the killing effect of ETS on HepG2 cells was significantly attenuated. ETS also inhibited phosphorylation of LAPTM4B-35 Tyr285, which involves in activation of the PI3K/Akt signaling pathway induced by LAPTM4B-35 overexpression. In addition, the induction of alterations in quantity of c-Myc, Bcl-2, Bax, cyclinD1 and Akt-p molecules in HepG2 cells by LAPTM4B-35 overexpression could be reversed by ETS. Conclusion: ETS is a promising candidate for treatment of HCC through LAPTM4B-35 protein targeting.

Highlights

LAPTM4B-35 (NP_060877) is encoded by Lysosomal protein transmembrane 4 beta (LAPTM4B, NM_018407), which was first cloned and found to be a driver gene of hepatocellular carcinoma (HCC) in our laboratory [1, 2]
Our previous studies demonstrated that LAPTM4B-35 is overexpressed in a variety of solid cancers including hepatocellular carcinoma (HCC), and is an independent factor for prognosis
Bel-7402 and HepG2 cell lines from human HCC were used as cell models in which LAPTM4B-35 is highly expressed, and a human fetal liver cell line was used as a control

Summary

Introduction

LAPTM4B-35 (NP_060877) is encoded by Lysosomal protein transmembrane 4 beta (LAPTM4B, NM_018407), which was first cloned and found to be a driver gene of hepatocellular carcinoma (HCC) in our laboratory [1, 2]. Growth and metastasis of xenograft from the human HCC cell line Bel-7402 in BALB\c-nude mice treated with ETS was significantly decreased, and the volume of tumor was notably reduced as compared with the solvent control and blank control (Figure 2a and 2b left panel).

Results

Conclusion