Spermidine/spermine N1-acetyltransferase regulates cell growth and metastasis via AKT/β-catenin signaling pathways in hepatocellular and colorectal carcinoma cells.

Cong Wang,Qian Li,Shasha Wang,Dong Fang,Jiuzhou Hou,Ping Ruan,Xiaoxiao Wu,Songqiang Xie,Xiaomin Li,Fujun Dai,Ying Zhao,Chaojie Wang,Tong Liu,Wei Li,Jun Wang,Jinghua Li

doi:10.18632/oncotarget.13582

Abstract

Hepatocellular carcinoma (HCC) and colorectal cancer (CRC) are among the most common cancers across the world. Therefore, identifying the potential molecular mechanisms that promote HCC and CRC progression and metastasis are urgently needed. Spermidine/spermine N1-acetyltransferase (SSAT) is a catabolic enzyme that acetylates the high-order polyamines spermine and spermidine, thus decreasing the cellular content of polyamines. Several publications have suggested that depletion of intracellular polyamines inhibited tumor progression and metastasis in various cancer cells. However, whether and how SSAT regulates cell growth, migration and invasion in hepatocellular and colorectal carcinoma cells remains unclear. In this study, depletion of polyamines mediated by SSAT not only attenuated the tumor cell proliferation but also dramatically inhibited cell migration and invasion in hepatocellular and colorectal carcinoma cells. Subsequent investigations revealed introduction of SSAT into HepG2, SMMC7721 hepatocellular carcinoma cells and HCT116 colorectal carcinoma cells significantly suppressed p-AKT, p-GSK3β expression as well as β-catenin nuclear translocation, while inhibition of GSK3β activity or exogenous polyamines could restore SSAT-induced decreases in the protein expression of p-AKT, p-GSK3β and β-catenin. Conversely, knockdown of SSAT in Bel7402 hepatocellular carcinoma cells and HT-29 colorectal carcinoma cells which expressed high levels of SSAT endogenously significantly promoted the expression of p-AKT, p-GSK3β as well as β-catenin nuclear translocation. Taken together, our results indicated depletion of polyamines by SSAT significantly inhibited cell proliferation, migration and invasion through AKT/GSK3β/β-catenin signaling pathway in hepatocellular carcinoma and colorectal cancer cells.

Highlights

Hepatocellular carcinoma (HCC) and colorectal cancer (CRC) are among the most common cancers across the world [1, 2]
Our results showed that after treatment with 5 mM Lithium chloride (LiCl) for 48 h, the expression of phosphorylated Glycogen synthase kinase 3β (GSK3β) was increased in SMMC7721, HepG2 and HCT116 cells transfected with SSAT (Figure 8A)
In order to investigate whether inhibition of GSK3β activity could restore SSAT-induced cell growth and invasion progress in hepatocellular and colorectal carcinoma cells, we performed the MTT cell viability assay and Boyden chamber transwell assay in the absence or presence of LiCl in SMMC7721, HepG2 and HCT116 cells transfected with SSAT

Summary

Introduction

Hepatocellular carcinoma (HCC) and colorectal cancer (CRC) are among the most common cancers across the world [1, 2]. Despite some advances in early detection and the use of modern surgical techniques in combination with radiotherapy and chemotherapy, the prognosis of the patients with HCC and CRC still remains poor to date [4, 5]. It has been well established that an increase in intracellular polyamine concentration correlates with increased cell proliferation as well as tumorigenesis. Increased polyamine concentrations are often observed in the blood and urine of cancer patients, and these increased levels have been shown to correlate with poor prognosis [8,9,10,11]. Depletion of the intracellular polyamine pools using either a polyamine synthesis inhibitor or a polyamine analog invariably inhibits cell growth in breast, colon, prostate and skin cancers [12,13,14,15,16]

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Results

Conclusion