Active form of AKT controls cell proliferation and response to apoptosis in hepatocellular carcinoma

Kunter,Imge; Erdal,Esra; Nart,Deniz; Yilmaz,Funda; Karademir,Sedat; Sagol,Ozgul; Atabey,Nese

doi:10.3892/or.2013.2932

Active form of AKT controls cell proliferation and response to apoptosis in hepatocellular carcinoma

Authors:
- Imge Kunter
- Esra Erdal
- Deniz Nart
- Funda Yilmaz
- Sedat Karademir
- Ozgul Sagol
- Nese Atabey
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Affiliations: Department of Medical Biology and Genetics, Faculty of Medicine, Dokuz Eylul University, Inciralti, Izmir 35340, Turkey, Department of Pathology, Faculty of Medicine, Ege University, Bornova, Izmir 35100, Turkey, Department of General Surgery, Faculty of Medicine, Dokuz Eylul University, Inciralti, Izmir 35340, Turkey, Department of Pathology, Faculty of Medicine, Dokuz Eylul University, Inciralti, Izmir 35340, Turkey
Published online on: December 16, 2013 https://doi.org/10.3892/or.2013.2932
Pages: 573-580
Copyright: © Kunter et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

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Abstract

Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related mortality worldwide. Deregulation of the AKT signaling pathway has been found in HCC. However, the effect of AKT activation on the proliferation and apoptosis in HCC is not clear. Herein, expression of phosphorylated form of AKT (Ser 473) was investigated in HCC tumor (n=73), cirrhosis (n=17), normal liver (n=22) samples and in HCC cell lines (n=8). The results showed that expression of p-AKT was higher in tumor (53%) than in cirrhotic tissues (12%) while it was absent in normal liver (p<0.0001). p-AKT expression was also associated with number of tumor nodules and differentiation status (p<0.05). LY294002 induced cell cycle arrest at G0/G1 in SNU-449 and Mahlavu cells by decreasing expression of CDK2, CDK4, CycD1, CycD3, CycE, CycA and increasing expression of p21 and p27 as well; it also caused a decrease in the E2F1 transcriptional activity through declining phosphorylated Rb. LY294002 did not affect the basal level of apoptosis; however, it amplified cisplatin-induced apoptosis in SNU-449 cells. When the p-AKT level was decreased specifically after transfection with the DN-AKT plasmid, SNU-449 cells became more sensitive to cisplatin-induced apoptosis. HuH-7 cells with no basal p-AKT, were markedly affected by the treatment of doxorubicin. Thus, Akt signaling controls growth and chemical-induced apoptosis in HCC and p-AKT may be a potential target for therapeutic interventions in HCC patients.

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