Faculty Collaboration Database

MK2206 inhibits hepatocellular carcinoma cellular proliferation via induction of apoptosis and cell cycle arrest. J Surg Res 2014 Oct;191(2):280-5

Date

07/06/2014

Pubmed ID

24996256

DOI

10.1016/j.jss.2014.05.083

Scopus ID

2-s2.0-84908254093 (requires institutional sign-in at Scopus site)   24 Citations

Abstract

BACKGROUND: Hepatocellular carcinoma (HCC) is commonly diagnosed at an advanced stage and has limited effective treatment options. The aberrant regulation of the phosphoinositide 3-kinase/Akt pathway in HCC makes it an attractive therapeutic target. The effect of MK2206, a novel, allosteric Akt inhibitor, on HCC cells is not yet fully understood. We hypothesized that inhibition of Akt by MK2206 would impact cellular viability.

MATERIALS AND METHODS: Human Huh7, Hep3B, and HepG2 cell lines were treated with 0-2 μM of MK2206 for 96 h. Cell viability was determined by using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Western blot analysis was used to examine the expression level of various protein markers to assess the mechanism of drug action and proliferation inhibition.

RESULTS: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay showed a reduction in cellular viability by ≥55% for all cell lines (control versus 2 μM MK2206; P <0.001). Western blot analysis revealed reduction in the level of phosphorylated AKT-Ser473 with no change in AKT-thr308 expression confirming the specificity of MK2206. There was an observed reduction in caspase-9 and survivin. Importantly, there were increases in p21 and p27 along with decreased cyclinD1 expression after treatment.

CONCLUSIONS: This study demonstrates the anti-tumor activity of MK2206 in HCC cells. The observed reduction in survivin and pro-caspase 9 suggests that MK2206 induces apoptosis. However, HCC proliferation is also halted via induction of cell cycle arrest as indicated by the increase in p21 and p27 expression and decrease in cyclinD1. Importantly, the concentration needed to achieve growth inhibition in HCC is lower than that needed for other cancer types.

Author List

Wilson JM, Kunnimalaiyaan S, Gamblin TC, Kunnimalaiyaan M

Author

Thomas Clark Gamblin MD Professor in the Surgery department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Apoptosis
Carcinoma, Hepatocellular
Cell Cycle Checkpoints
Cell Line, Tumor
Cell Proliferation
Heterocyclic Compounds, 3-Ring
Humans
Liver Neoplasms
Proto-Oncogene Proteins c-akt