mTOR is a promising therapeutical target in a subpopulation of pancreatic adenocarcinoma

Utomo, Wesley K.; Narayanan, Vilvapathy; Biermann, Katharina; Eijck, Casper H.J. van; Bruno, Marco J.; Peppelenbosch, Maikel P.; Braat, Henri

doi:10.1016/j.canlet.2014.01.014

Cited by 22 publications

(13 citation statements)

References 43 publications

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“…The limitations of the study are its retrospective design, the associated bias and the small number of samples in the study in pancreatic cancer patients with diabetes who underwent pancreatic cancer resection. It has been documented that whether patients benefit from mTOR inhibitor depends on the status of mTOR activation in patients with pancreatic cancer 54 , and P70S6K has been documented to be the major direct target of mTORC1 that mediates the anticancer actions of mTOR inhibitors 14 . Thus, patients with P70S6K signaling activation should benefit more from metformin.…”

Section: Discussionmentioning

confidence: 99%

Metformin Increases Sensitivity of Pancreatic Cancer Cells to Gemcitabine by Reducing CD133+ Cell Populations and Suppressing ERK/P70S6K Signaling

Chai

Chu

Yang

et al. 2015

Sci Rep

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The prognosis of pancreatic cancer remains dismal, with little advance in chemotherapy because of its high frequency of chemoresistance. Metformin is widely used to treat type II diabetes, and was shown recently to inhibit pancreatic cancer stem cell proliferation. In the present study, we investigated the role of metformin in chemoresistance of pancreatic cancer cells to gemcitabine, and its possible cellular and molecular mechanisms. Metformin increases sensitivity of pancreatic cancer cells to gemcitabine. The mechanism involves, at least in part, the inhibition of CD133+ cells proliferation and suppression of P70S6K signaling activation via inhibition of ERK phosphorylation. Studies of primary tumor samples revealed a relationship between P70S6K signaling activation and the malignancy of pancreatic cancer. Analysis of clinical data revealed a trend of the benefit of metformin for pancreatic cancer patients with diabetes. The results suggested that metformin has a potential clinical use in overcoming chemoresistance of pancreatic cancer.

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Section: Discussionmentioning

confidence: 99%

Metformin Increases Sensitivity of Pancreatic Cancer Cells to Gemcitabine by Reducing CD133+ Cell Populations and Suppressing ERK/P70S6K Signaling

Chai

Chu

Yang

et al. 2015

Sci Rep

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“…The mTOR pathway is constitutively activated in 25%-75% of human PDAC tumors and mTOR inhibition can lead to proliferation arrest of PDAC cells [ 143 ]. Rapamycin induces autophagy in rapamycin-sensitive pancreatic cell lines only, which suggests that autophagy induction may be a downstream consequence of the antitumor effects of mTOR inhibitors [ 144 , 145 ]. Recent results from phase II clinical trials of mTOR inhibitors in PDAC patients failed to demonstrate clinical benefit [ 146 , 147 ].…”

Section: Targeting Metabolism In Pancreatic Cancermentioning

confidence: 99%

Targeting cancer cell metabolism in pancreatic adenocarcinoma

et al. 2015

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Pancreatic ductal adenocarcinoma (PDAC) is expected to become the second leading cause of cancer death by 2030. Current therapeutic options are limited, warranting an urgent need to explore innovative treatment strategies. Due to specific microenvironment constraints including an extensive desmoplastic stroma reaction, PDAC faces major metabolic challenges, principally hypoxia and nutrient deprivation. Their connection with oncogenic alterations such as KRAS mutations has brought metabolic reprogramming to the forefront of PDAC therapeutic research. The Warburg effect, glutamine addiction, and autophagy stand as the most important adaptive metabolic mechanisms of cancer cells themselves, however metabolic reprogramming is also an important feature of the tumor microenvironment, having a major impact on epigenetic reprogramming and tumor cell interactions with its complex stroma. We present a comprehensive overview of the main metabolic adaptations contributing to PDAC development and progression. A review of current and future therapies targeting this range of metabolic pathways is provided.

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“…Given the up-regulation of the mTOR pathway in many chemoresistant cancer [2] , mTOR inhibitors provide a logical solution to re-sensitize tumor cells to chemotherapy or to delay the development of resistance to treatment. Recent studies have demonstrated the effectiveness of sirolimus (rapamycin) in solid tumors, such as metastatic breast [3] , pancreatic [4] , and renal carcinomas [5] . Sirolimus is a first generation mTOR inhibitor [6][7][8] .…”

Section: Introductionmentioning

confidence: 99%

Sirolimus induces apoptosis and reverses multidrug resistance in human osteosarcoma cells in vitro via increasing microRNA-34b expression

et al. 2016

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Aim: Multi-drug resistance poses a critical bottleneck in chemotherapy. given the up-regulation of mToR pathway in many chemoresistant cancers, we examined whether sirolimus (rapamycin), a first generation mTOR inhibitor, might induce human osteosarcoma (os) cell apoptosis and increase the sensitivity of os cells to anticancer drugs in vitro. Methods: human os cell line Mg63/aDM was treated with sirolimus alone or in combination with doxorubicin (aDM), gemcitabine (GEM) or methotrexate (MTX). Cell proliferation and apoptosis were detected using CCK-8 assay and flow cytometry, respectively. MiRnas in the cells were analyzed with miRna microarray. The targets of miR-34b were determined based on Targetscan analysis and luciferase reporter assays. The expression of relevant mRna and proteins was measured using qRT-PCR and Western blotting. MiR-34, PaK1 and aBCB1 levels in 40 tissue samples of os patients were analyzed using qRT-PCR and in situ hybridization assays. Results: Sirolimus (1−100 nmol/L) dose-dependently suppressed the cell proliferation (IC 50 =23.97 nmol/L) and induced apoptosis. Sirolimus (10 nmol/L) significantly sensitized the cells to anticancer drugs, leading to decreased IC 50 values of aDM, geM and MTX (from 25.48, 621.41 and 21.72 μmol/L to 4.93, 73.92 and 6.77 μmol/L, respectively). Treatment of with sirolimus increased miR-34b levels by a factor of 7.5 in the cells. upregulation of miR-34b also induced apoptosis and increased the sensitivity of the cells to the anticancer drugs, whereas transfection with miR-34b-aMo, an inhibitor of miR-34b, reversed the anti-proliferation effect of sirolimus. Two key regulators of cell cycle, apoptosis and multiple drug resistance, PaK1 and aBCB1, were demonstrated to be the direct targets of miR-34b. In 40 tissue samples of OS patients, significantly higher miR-34 ISH score and lower PAK5 and ABCB1 scores were detected in the chemo-sensitive group. Conclusion: sirolimus increases the sensitivity of human os cells to anticancer drugs in vitro by up-regulating miR-34b interacting with PaK1 and aBCB1. a low miR-34 level is an indicator of poor prognosis in os patients.

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mTOR is a promising therapeutical target in a subpopulation of pancreatic adenocarcinoma

Cited by 22 publications

References 43 publications

Metformin Increases Sensitivity of Pancreatic Cancer Cells to Gemcitabine by Reducing CD133+ Cell Populations and Suppressing ERK/P70S6K Signaling

Metformin Increases Sensitivity of Pancreatic Cancer Cells to Gemcitabine by Reducing CD133+ Cell Populations and Suppressing ERK/P70S6K Signaling

Targeting cancer cell metabolism in pancreatic adenocarcinoma

Sirolimus induces apoptosis and reverses multidrug resistance in human osteosarcoma cells in vitro via increasing microRNA-34b expression

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