scholarly journals SC06, a novel small molecule compound, displays preclinical activity against multiple myeloma by disrupting the mTOR signaling pathway

2015 ◽  
Vol 5 (1) ◽  
Author(s):  
Kunkun Han ◽  
Xin Xu ◽  
Zhuan Xu ◽  
Guodong Chen ◽  
Yuanying Zeng ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Signaling Pathway ◽  
Small Molecule ◽  
Mtor Signaling ◽  
Mtor Signaling Pathway ◽  
Small Molecule Compound

scholarly journals A Small Molecule Screen Exposes mTOR Signaling Pathway Involvement in Radiation-Induced Apoptosis

2016 ◽  
Vol 11 (5) ◽  
pp. 1428-1437 ◽  
Author(s):  
Elizabeth R. Sharlow ◽  
Stephanie Leimgruber ◽  
Ana Lira ◽  
Michael J. McConnell ◽  
Andrés Norambuena ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Small Molecule ◽  
Mtor Signaling ◽  
Mtor Signaling Pathway ◽  
Small Molecule Screen ◽  
Radiation Induced ◽  
Induced Apoptosis

MLN4924, An Investigational NAE Inhibitor, Suppresses AKT and mTOR Signaling Pathway Through up Regulating REDD1 in Human Myeloma Cells

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1870-1870
Author(s):  
Yanyan Gu ◽  
Jonathan L. Kaufman ◽  
Lawrence H. Boise ◽  
Sagar Lonial
Keyword(s):  
Multiple Myeloma ◽  
Western Blot ◽  
Signaling Pathway ◽  
Cell Lines ◽  
Research Funding ◽  
Myeloma Cell ◽  
Mtor Pathway ◽  
Mtor Signaling ◽  
Mtor Signaling Pathway ◽  
Myeloma Cells

Abstract Abstract 1870 Introduction: The development and survival of normal plasma cells as well as multiple myeloma cells depend on an elaborately regulated ubiquitin proteasome system (UPS). Proteasome inhibitors such as bortezomib have proved to be highly active in the treatment of multiple myeloma. MLN4924, a newly developed investigational NEDD8 activating enzyme (NAE) inhibitor, exhibits promising anti-tumor effect through both clinical and laboratory observation. We sought to evaluate the individual signaling effects of MLN4924 in multiple myeloma, with the intent of further understanding the mechanism of action and identifying potential combinations. Methods: Human myeloma cell lines (MM.1S, MM.1R and U266) were treated with increasing concentrations of MLN4924 for 24, 48 and 72 hrs respectively or concurrently with bortezomib. Cell viability (MTT), apoptosis, western blot, RT-qPCR and siRNA assays were used to identify the cellular and molecular sequelae of MLN4924 treatment. Results: Single agent studies demonstrate that MLN4924 induces cytotoxicity in all three MM cell lines. Cytotoxicity is associated with increased apoptosis and suppression of AKT and mTOR signaling pathway, as detected by FACS and western blot. MLN4924 suppresses protein turnover of Cullin-ring ligases substrates leading to stabilization of specific proteins, such as p27, CDT1, NRF2. We find that REDD1, a substrate of CUL4 A–DDB 1–ROC1–β-TRCP ubiquitin ligase and negative regulator of mTOR pathway, increases in as early as 2 hours when treated with MLN4924. Knock-down of REDD1 using siRNA alleviates MLN4924 induced AKT, mTOR signaling suppression as well as the growth inhibition, which suggests that MLN4924 inhibits AKT, mTOR signaling through upregulating REDD1 protein leading to cytotoxicity. Combining MLN4924 with bortezomib synergistically enhances the antitumor effect of MLN4924. Western blot confirms the development of significantly increased procaspase and PARP cleavage, as well as substantial down regulation of AKT and mTOR signaling. Neither IL-6 nor IGF-1 is able to abrogate these combination effects. When we silence REDD1 in the combination assay in MM.1R, we find less cell apoptosis and suppression of AKT, mTOR pathway, which further support that REDD1 is an important regulator for MLN4924 induced cytotoxicity in MMs. Conclusion: MLN4924 is a potent investigational antitumor compound suppressing mTOR signaling pathways in myeloma cell lines. Down-regulation of the mTOR signaling pathway is associated with increased expression of REDD1. Combination of MLN4924 with the proteasome inhibitor bortezomib induces synergistic apoptosis in MMs cell lines which can overcome the prosurvival effects of growth factor (IL-6 and IGF-1). These findings could positively impact clinical combination strategies. Disclosures: Kaufman: Millenium: Consultancy; Onyx Pharmaceuticals: Consultancy; Novartis: Consultancy; Keryx: Consultancy; Merck: Research Funding; Celgene: Research Funding. Lonial:Millennium Pharmaceuticals, Inc.: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Bristol-Myers Squibb: Consultancy; Onyx: Consultancy; Merck: Consultancy.

scholarly journals MicroRNA-451 regulates stemness of side population cells via PI3K/Akt/mTOR signaling pathway in multiple myeloma

Oncotarget ◽  
2015 ◽  
Vol 6 (17) ◽  
pp. 14993-15007 ◽  
Author(s):  
Juan Du ◽  
Shuyan Liu ◽  
Jie He ◽  
Xi Liu ◽  
Ying Qu ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Signaling Pathway ◽  
Side Population ◽  
Mtor Signaling ◽  
Mtor Signaling Pathway ◽  
Side Population Cells
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