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High GSTP1 inhibits cell proliferation by reducing Akt phosphorylation and is associated with a better prognosis in hepatocellular carcinoma.

ABSTRACT: Glutathione S-transferase (GST) family members promote carcinogenesis and cancer progression. We assessed GST pi 1 (GSTP1) mRNA and protein levels in hepatocellular carcinoma (HCC) using genome databases and tissue microarray (TMA) technology. We found that in cancerous tissues, GSTP1 mRNA was down-regulated in genome databases, and immunohistochemical staining of GSTP1 in 237 HCC cases varied from negative to strongly positive. GSTP1 levels correlated negatively with tumor size and serum alpha-fetoprotein (AFP) in HCC patients, and higher GSTP1 levels associated with longer overall survival (OS) and disease-free survival (DFS). We also found that GSTP1 overexpression restrained HepG2 and Huh7 liver cancer cell proliferation in vivo and in vitro. GSTP1 arrested the cell cycle at G1/S by up-regulating p21 and p27 and down-regulating p-Akt. Interrupting GSTP1 gene expression promoted liver cancer cell proliferation and increased the percentage of cells in S phase by decreasing levels of p21 and p27 and increasing p-Akt. These results suggest high GSTP1 levels provide a better prognosis through suppression of tumorigenesis in HCC.

SUBMITTER: Liu X

PROVIDER: S-EPMC5823662 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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High GSTP1 inhibits cell proliferation by reducing Akt phosphorylation and is associated with a better prognosis in hepatocellular carcinoma.

Liu Xiaojia X Tan Ning N Liao Hongtao H Pan Guangdong G Xu Qing Q Zhu Rong R Zou Liping L He Songqing S Zhu Hongguang H

Oncotarget 20171219 10

Glutathione S-transferase (GST) family members promote carcinogenesis and cancer progression. We assessed GST pi 1 (GSTP1) mRNA and protein levels in hepatocellular carcinoma (HCC) using genome databases and tissue microarray (TMA) technology. We found that in cancerous tissues, GSTP1 mRNA was down-regulated in genome databases, and immunohistochemical staining of GSTP1 in 237 HCC cases varied from negative to strongly positive. GSTP1 levels correlated negatively with tumor size and serum alpha- ...[more]

PMID: 29507666

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Project description:BackgroundDue to the frequent dysregulation of the PI3K/AKT/mTOR signaling pathway, mTOR represents a suitable therapeutic target in hepatocellular carcinoma (HCC). However, emerging data from clinical trials of HCC patients indicate that mTOR inhibition by RAD001 (Everolimus) alone has only moderate antitumor efficacy which may be due to the feedback activation of AKT after mTOR inhibition. In this study, we analyzed the effects of dual inhibition of mTOR and AKT on the proliferation of HCC cell lines. In addition, we measured the feedback activation of each of the AKT isoforms after mTOR inhibition in HCC cell lines and their enzymatic activity in primary samples from HCC patients.MethodsThe activation status of specific AKT isoforms in human HCC samples and corresponding healthy liver tissue was analyzed using an AKT isoform specific in vitro kinase assay. AKT isoform activation after mTOR inhibition was analyzed in three HCC cell lines (Hep3B, HepG2 and Huh7), and the impact of AKT signaling on proliferation after mTOR inhibition was investigated using the novel AKT inhibitor MK-2206 and AKT isoform specific knockdown cells.ResultsAKT isoforms become differentially activated during feedback activation following RAD001 treatment. The combination of mTOR inhibition and AKT isoform knockdown showed only a weak synergistic effect on proliferation of HCC cell lines. However, the combinatorial treatment with RAD001 and the pan AKT inhibitor MK-2206 resulted in a strong synergism, both in vitro and in vivo. Moreover, by analyzing primary HCC tissue samples we were able to demonstrate that a hotspot mutation (H1047R) of PI3KCA, the gene encoding the catalytic subunit of PI3K, was associated with increased in vitro kinase activity of all AKT isoforms in comparison to healthy liver tissue of the patient.ConclusionOur results demonstrate that dual targeting of mTOR and AKT by use of RAD001 and the pan AKT inhibitor MK-2206 does effectively inhibit proliferation of HCC cell lines. These data suggest that combined treatment with RAD001 and MK-2206 may be a promising therapy approach in the treatment of hepatocellular carcinoma.

Dataset Information

High GSTP1 inhibits cell proliferation by reducing Akt phosphorylation and is associated with a better prognosis in hepatocellular carcinoma.

Publications

High GSTP1 inhibits cell proliferation by reducing Akt phosphorylation and is associated with a better prognosis in hepatocellular carcinoma.

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