| Reference | 1. Oncol Rep. 2015 Oct;34(4):1708-16. doi: 10.3892/or.2015.4146. Epub 2015 Jul 23.
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The novel mTOR inhibitor Torin-2 induces autophagy and downregulates the
expression of UHRF1 to suppress hepatocarcinoma cell growth.
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Wang C(1), Wang X(2), Su Z(1), Fei H(1), Liu X(1), Pan Q(1).
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Author information: <br>
(1)Department of Surgical Oncology, The First Hospital of Quanzhou Affiliated to
Fujian Medical University, Fujian, Quanzhou 362000, P.R. China.
(2)Department of Obstetrics and Gynecology, The Second Affiliated Hospital of
Fujian Medical University, Fujian, Quanzhou 362000, P.R. China.
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Mammalian target of rapamycin (mTOR) is frequently upregulated in hepatocellular
carcinoma (HCC). Blockage of mTOR was found to induce marked reduction in HCC
growth in preclinical models. In the present study, we tested a novel mTOR
inhibitor, Torin-2, for its antitumor efficacy in HCC cell lines Hep G2, SNU-182
and Hep 3B2.1-7. The HCC cell lines were cultured in vitro. These cells were
treated with Torin-2. Cell apoptosis was evaluated by Annexin V staining. Cell
proliferation and cell cycle progression were determined by Ki67 staining and
propidium iodide staining, respectively. mTOR signaling, autophagy induction and
expression of ubiquitin-like containing PHD and RING finger domains 1 (UHRF1)
were assessed by western blot analysis. The UHRF1 mRNA level was determined by
real-time PCR. We found that Torin-2 effectively suppressed the growth and
survival of HCC cell lines, demonstrated by reduced proliferation and a high rate
of apoptosis. Further study elucidated that in addition to blocking mTOR complex
1 (mTORC1)-associated cell cycle progression and induction of autophagy, Torin-2
downregulated transcription of UHRF1, an essential regulator of DNA methylation
that is highly expressed in HCC cell lines. Consistently, the level of DNA
(cytosine-5)-methyltransferase 1 (DNMT1) was higher after treatment of the HCC
cell lines with Torin-2. The downregulation of UHRF1 by Torin-1 was partially due
to a decrease in the UHRF1 mRNA level. Torin-2 effectively inhibited HCC cell
proliferation through induction of autophagy. Torin‑2-induced downregulation of
UHRF1 expression may also contribute to its antitumor effect. Our research
provides new clues regarding the antitumor effects of Torin-2 and sheds light on
a novel therapeutic approach for HCC.
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2. Oncotarget. 2014 Oct 30;5(20):10034-47.
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Activity of the novel mTOR inhibitor Torin-2 in B-precursor acute lymphoblastic
leukemia and its therapeutic potential to prevent Akt reactivation.
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Simioni C(1), Cani A(1), Martelli AM(2), Zauli G(3), Tabellini G(4), McCubrey
J(5), Capitani S(6), Neri LM(1).
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Author information: <br>
(1)Department of Morphology, Surgery and Experimental Medicine, University of
Ferrara, Ferrara, Italy.
(2)Department of Biomedical and Neuromotor Sciences, University of Bologna,
Bologna, Italy.
(3)Institute for Maternal and Child Health, IRCCS /Burlo Garofolo/, Trieste,
Italy.
(4)Department of Molecular and Translational Medicine, University of Brescia,
Brescia, Italy.
(5)Department of Microbiology and Immunology, Brody School of Medicine, East
Carolina University, Greenville, NC, USA.
(6)Department of Morphology, Surgery and Experimental Medicine, University of
Ferrara, Ferrara, Italy. LTTA Center, University of Ferrara, Ferrara, Italy.
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The PI3K/Akt/mTOR signaling cascade is a key regulatory pathway controlling cell
growth and survival, and its dysregulation is a reported feature of B-precursor
acute lymphoblastic leukemia (B-pre ALL). Torin-2 is a novel, second-generation
ATP-competitive inhibitor that is potent and selective for mTOR with a superior
pharmacokinetic profile to previous inhibitors. It has been shown that Torin-2
displayed dramatic antiproliferative activity across a panel of cancer cell
lines. To investigate if Torin-2 could represent a new option for the treatment
of B-pre ALL, we tested its activity on a panel of B-pre ALL cell lines. In all
of them Torin-2 showed a powerful cytotoxic activity, inhibiting the growth of
each cell line in a dose-dependent manner, with an IC₅₀ in the nanomolar range.
Torin-2 caused both apoptosis and autophagy, induced cell cycle arrest in G₀/G₁
phase and affected both mTORC1 and mTORC2 activities as assessed by their
specific substrate dephosphorylation. Torin-2 alone suppressed feedback
activation of PI3K/Akt, whereas the mTORC1 inhibitor RAD001 required the addition
of the Akt inhibitor MK-2206 to achieve the same effect. These pharmacological
strategies targeting PI3K/Akt/mTOR at different points of the signaling pathway
cascade might represent a new promising therapeutic strategy for treatment of
B-pre ALL patients.
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