Spermidine/spermine N1-acetyltransferase regulates cell growth and metastasis via AKT/β-catenin signaling pathways in hepatocellular and colorectal carcinoma cells.
Spermidine/spermine N1-acetyltransferase regulates cell growth and metastasis via AKT/β-catenin signaling pathways in hepatocellular and colorectal carcinoma cells.
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精胺/精胺 N1-乙酰转移酶通过 AKT/β-连环蛋白信号通路调节肝细胞和结直肠癌细胞中的细胞生长和转移
DOI：
10.18632/oncotarget.13582
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发表时间：
2017-01-03
期刊：
影响因子：
--
通讯作者：
Xie S
中科院分区：
文献类型：
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作者：
Wang C;Ruan P;Zhao Y;Li X;Wang J;Wu X;Liu T;Wang S;Hou J;Li W;Li Q;Li J;Dai F;Fang D;Wang C;Xie S
肝细胞癌（HCC）和结直肠癌（CRC）是全球最常见的癌症类型之一。因此，迫切需要确定促进肝细胞癌和结直肠癌进展及转移的潜在分子机制。亚精胺/精胺N1-乙酰基转移酶（SSAT）是一种分解代谢酶，可使高阶多胺精胺和亚精胺乙酰化，从而降低细胞内多胺含量。多项研究表明，细胞内多胺耗竭可抑制多种癌细胞的肿瘤进展和转移。然而，SSAT是否以及如何调节肝癌细胞和结肠癌细胞的生长、迁移和侵袭仍不清楚。
在本研究中，由SSAT介导的多胺耗竭不仅减弱了肿瘤细胞的增殖，还显著抑制了肝癌细胞和结肠癌细胞的迁移和侵袭。后续研究发现，将SSAT导入HepG2、SMMC7721肝癌细胞和HCT116结肠癌细胞后，可显著抑制p-AKT、p-GSK3β的表达以及β-连环蛋白的核转位，而抑制GSK3β活性或添加外源性多胺可恢复SSAT诱导的p-AKT、p-GSK3β和β-连环蛋白蛋白表达的降低。相反，在内源性高表达SSAT的Bel7402肝癌细胞和HT-29结肠癌细胞中敲低SSAT，可显著促进p-AKT、p-GSK3β的表达以及β-连环蛋白的核转位。
综上所述，我们的研究结果表明，SSAT介导的多胺耗竭通过AKT/GSK3β/β-连环蛋白信号通路，显著抑制了肝癌细胞和结肠癌细胞的增殖、迁移和侵袭。
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.