Role of Akt inhibition on Notch1 expression in hepatocellular carcinoma: potential role for dual targeted therapy

Abstract Background We have shown that an Akt inhibitor, MK2206, reduces hepatocellular carcinoma (HCC) proliferation. To further delineate MK2206, we sought to investigate the Notch1 pathway and hypothesize that MK2206 treatment will result in Notch1 inhibition with either subsequent or parallel Ak...

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Bibliographic Details
Published in:The American journal of surgery 2016-04, Vol.211 (4), p.755-760
Main Authors: Sokolowski, Kevin M., M.D, Balamurugan, Mariappan, Ph.D, Kunnimalaiyaan, Selvi, M.S, Wilson, Jacob, B.S, Gamblin, Thomas Clark, M.D., M.S., M.B.A., F.A.C.S, Kunnimalaiyaan, Muthusamy, Ph.D
Format: Article
Language:English
Subjects:
Akt
Blotting, Western
Carcinoma, Hepatocellular - pathology
Cell Line, Tumor
Cell Proliferation - drug effects
Cell Survival - drug effects
Clinical trials
Dual target
Hepatocellular carcinoma
Heterocyclic Compounds, 3-Ring - pharmacology
Humans
Kinases
Liver cancer
Liver Neoplasms - pathology
MK2206
Mortality
Notch
Phosphorylation
Proto-Oncogene Proteins c-akt - antagonists & inhibitors
Receptor, Notch1 - metabolism
Signal Transduction - drug effects
Studies
Surgery
Tumors
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Summary:Abstract Background We have shown that an Akt inhibitor, MK2206, reduces hepatocellular carcinoma (HCC) proliferation. To further delineate MK2206, we sought to investigate the Notch1 pathway and hypothesize that MK2206 treatment will result in Notch1 inhibition with either subsequent or parallel Akt suppression. Methods HCC cell lines were treated with various concentrations of MK2206. Cell proliferation was determined via real-time live cell imaging. Knockdown of Notch1 was used to observe interaction between Notch1 and pAkt. Cell lysates were analyzed via Western blotting for Notch and Akt pathway targets. Results After treatment with MK2206 (up to 2 μM), there was a 60% reduction in cell viability at 48 hours with a concomitant reduction in Notch1 expression. Knockdown of Notch1 in HCC cell lines correlated with reduction in Akt phosphorylation. Conclusions MK2206 inhibits both the PI3-K/Akt and Notch1 pathways. Therefore, further characterization of MK2206 comparing the 2 pathways is warranted and the effect of dual targeting in HCC.
ISSN:0002-9610
1879-1883
DOI:10.1016/j.amjsurg.2015.11.029