The Expression of Phospho-AKT, Phospho-mTOR, and PTEN in Extrahepatic Cholangiocarcinoma

Chung, Joon‐Yong; Hong, Seung‐Mo; Choi, Byung-Il; Cho, HyungJun; Yu, Eunsil; Hewitt, Stephen M.

doi:10.1158/1078-0432.ccr-08-1084

Cited by 107 publications

(88 citation statements)

References 39 publications

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“…Metformin inhibited the activation of the mTORC1 by activating AMPK in RBE and HCCC-9810 cells in our study. Although it remains controversial whether activation of mTOR pathway promotes development of cholangiocarcinoma or predicts poor prognosis in patients with cholangiocarcinoma (19,20), our results are in line with numerous other reports describing the inhibitory effect of metformin on cancer cells (6,10,21).…”

Section: Discussionsupporting

confidence: 92%

Metformin inhibits proliferation and enhances chemosensitivity of intrahepatic cholangiocarcinoma cell lines

Ling

Feng

et al. 2014

Oncology Reports

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Abstract.Metformin is an oral anti-hyperglycemic agent of the biguanide family, which is used first-line for type II diabetes with few side-effects. A recent epidemiological study that included 1,828 potential intrahepatic cholangiocarcinoma (ICC) patients showed that metformin use was significantly associated with a 60% reduction in ICC risk in diabetic patients, demonstrating the potential value of metformin in ICC management. In the present study, we firstly showed that metformin exhibited a dose-and time-dependent anti-proliferation effect on ICC cell lines, by mechanisms including apoptosis induction and cell cycle arrest. Metformin targeted the AMPK/mTORC1 pathway in ICC cells. Furthermore, metformin sensitized ICC cells to certain chemotherapeutic agents, such as sorafenib, 5-fluorouracil and As 2 O 3 by targeting the AMPK/mTOR/ HIF-1α/MRP1 pathway and ERK. As it is an inexpensive and widely used antidiabetic drug without severe adverse effects, metformin may be a prospective chemotherapeutic agent or a chemosensitizer in future ICC treatment. IntroductionMetformin, a first-line oral anti-type II diabetes agent used worldwide, displays an antitumorigenesis effect, according to recent epidemic studies (1-3). As compared to insulin or sulfonylureas administration, metformin use may markedly reduce the cancer risk in patients with type II diabetes. Recent studies have confirmed the anti-proliferation effect on various human cancer cell types, such as pancreas (4), prostate (5), breast (6), stomach (7) and liver (8). Metformin inhibits the pro-proliferation effect of insulin receptor-and IGF receptor-dependent signaling by reducing insulin resistance. Furthermore, metformin activates AMP-activated protein kinase (AMPK) and subsequently inhibits activation of mammalian target of rapamycin (mTOR) to prevent proliferation of tumor cells, and activates p53 protein-inducing cell cycle arrest of tumor cells. Several studies have indicated that metformin can potentiate the effect of chemotherapeutic agents or reverse drug resistance in cancer cells (8-10). However, the mechanism of the anti-cancer effects of metformin remains unclear.A recent epidemiological study that included 1,828 potential intrahepatic cholangiocarcinoma (ICC) patients described that metformin use was significantly associated with a 60% reduction in ICC risk in diabetic patients (11). Cholangiocarcinoma (CC)categorized as intrahepatic and extrahepatic cholangiocarcinoma (ECC) is highly lethal. ICC is the second most common type of primary liver cancer and its incidence and mortality rates have been rising in recent decades (12-15). Less than 30% of patients with ICC have the opportunity to have radical operation at diagnostic presentation. Apart from radical operation, some treatment approaches such as systemic chemotherapy, transarterial chemoembolization and radiofrequency ablation may be applied at advanced stages of ICC; however, none of the approaches can significantly improve the prognosis of ICC. Thus, new treatment strategies are needed ...

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Section: Discussionsupporting

confidence: 92%

Metformin inhibits proliferation and enhances chemosensitivity of intrahepatic cholangiocarcinoma cell lines

Ling

Feng

et al. 2014

Oncology Reports

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“…A recent study demonstrated that a low PTEN expression and decreased PTEN/p-AKT1 and PTEN/p-MTOR expression ratios in extrahepatic cholangiocarcinoma were poor prognostic factors, although there were no significant differences in survival rates based on the single protein expression status of p-AKT1 and p-MTOR. 25 Moreover, an earlier study demonstrated that PIK3CA is an important mediator of Ras-induced radiation resistance in T24 (human bladder carcinoma) cells, 26 and Tanno et al 27 drew a similar conclusion that constitutively active AKT1 markedly decreased radiosensitivity in human bile duct cancer cells. In contrast, in the present study, we found the overexpression of PTEN, p-AKT1, and p-MTOR could predict better survival in patients with intrahepatic cholangiocarcinoma.…”

Section: Discussionmentioning

confidence: 93%

The expression of phospho-AKT1 and phospho-MTOR is associated with a favorable prognosis independent of PTEN expression in intrahepatic cholangiocarcinomas

Lee

Choi

et al. 2012

Modern Pathology

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AKT1 signaling pathway is important for the regulation of protein synthesis and cell survival with implications in carcinogenesis. In this study, we explored the prognostic significance of AKT1 pathway in intrahepatic cholangiocarcinomas. We investigated the status of phosphatase and tensin homolog deleted on chromosome 10 (PTEN), phosphorylated (p) AKT1 (p-AKT1), p-mammalian target of rapamycin (p-MTOR), p-p70 ribosomal protein S6 kinase (p-RPS6KB2) and p-eukaryotic initiation factor 4E-binding protein-1 (p-EIF4EBP1) in 101 intrahepatic cholangiocarcinomas by immunohistochemistry. Western blot analysis was performed to verify the expression levels of p-AKT1 and p-MTOR. The relationship of protein expression with clinicopathological data and the correlations of protein expression levels were explored. The overexpression of p-AKT1, p-MTOR, and PTEN was associated with a better survival in patients with intrahepatic cholangiocarcinoma (P ¼ 0.0137, 0.0194, and 0.0337, respectively). In a multivariate analysis, PTEN was an independent prognostic factor, and p-AKT1 showed tendency (P ¼ 0.032 and 0.051, respectively). The overexpression of p-MTOR was correlated with well-to-moderately differentiated tumors (Po0.001) and tumors without metastasis (P ¼ 0.046). Expression levels of the AKT1 signaling pathway proteins in this study showed positive correlations with each other, except for PTEN. Aberrant expressions of p-AKT1 and p-MTOR in intrahepatic cholangiocarcinoma were associated with a favorable prognosis, possibly in a PTEN-independent manner. Our results indicate that dysregulation of the AKT1 pathway may have an important role in the development of intrahepatic cholangiocarcinoma, but not necessarily in the progression of the disease.

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“…Activated p-mTOR has been demonstrated to be associated with tumors in numerous cancer tissues. It has been found that the expression of the p-mTOR protein is elevated in extrahepatic cholangiocarcinoma (25) and the expression of the p-P70S6K protein is increased in high-grade squamous intraepithelial lesions and cervical squamous cell carcinoma compared with the normal cervical epithelium (22). In the present study, the rate of the positive expression of p-P70S6K and p-mTOR was detected to be significantly higher in colorectal cancer tissues compared with normal tissues.…”

Section: A B Discussionmentioning

confidence: 99%

Expression and clinical significance of mammalian target of rapamycin/P70 ribosomal protein S6 kinase signaling pathway in human colorectal carcinoma tissue

Wang

et al. 2015

Oncology Letters

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Abstract. The activation of mammalian target of rapamycin (mTOR) has been reported in tumor development, but the role of mTOR in colorectal carcinomas remains unclear. The aim of the present study was to investigate the significance of mTOR and its downstream effector 70 kDa ribosomal protein S6 kinase (P70S6K) in human colorectal carcinomas. The phosphorylated (p-)mTOR and p-P70S6K proteins were examined by immunohistochemistry performed on tissue microarray containing tissue samples obtained from colorectal carcinoma (n=111), adenomatous polyps (n=40) and normal colonic mucosa (n=40), with a comparison between the expression of these proteins and the clinicopathological parameters of patients with carcinomas. The positive expression rates of p-mTOR and p-P70S6k were 60.4 and 65.8%, respectively, in colorectal carcinoma tissue, which was significantly increased compared with the tissue from adenomatous polyps (27.5 and 20%, respectively) and normal colonic mucosa (10.0 and 5.0%, respectively) (P<0.05). Overexpression of the p-mTOR and p-P70S6K proteins was significantly associated with the tumor-node-metastasis stage, the occurrence of distal and lymph node metastasis and the degree of differentiation. Aberrant expression of p-mTOR and p-P70S6K may contribute to the pathogenesis, growth, invasion and metastasis of colorectal carcinoma. The phosphorylation of these proteins was considered to be a promising marker to indicate the aggressive behaviors and prognosis of colorectal carcinomas. The overexpression of the mTOR/P70S6K signaling pathway may play an important role in colorectal carcinoma carcinogenesis. The expression of p-mTOR and p-P70S6K was considered as a promising marker to indicate the aggressive behaviors and prognosis of human colorectal carcinomas.

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The Expression of Phospho-AKT, Phospho-mTOR, and PTEN in Extrahepatic Cholangiocarcinoma

Cited by 107 publications

References 39 publications

Metformin inhibits proliferation and enhances chemosensitivity of intrahepatic cholangiocarcinoma cell lines

Metformin inhibits proliferation and enhances chemosensitivity of intrahepatic cholangiocarcinoma cell lines

The expression of phospho-AKT1 and phospho-MTOR is associated with a favorable prognosis independent of PTEN expression in intrahepatic cholangiocarcinomas

Expression and clinical significance of mammalian target of rapamycin/P70 ribosomal protein S6 kinase signaling pathway in human colorectal carcinoma tissue

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