A small molecule compound inhibits AKT pathway in ovarian cancer cell lines

Huai Jing Tang, Xiaohong Jin, Shaomeng Wang, Dajun Yang, Yeyu Cao, Jianyong Chen, Dana R. Gossett, Jiayuh Lin*

*Corresponding author for this work

Research output: Contribution to journalArticle

33 Scopus citations

Abstract

Background and objective. Overactivation of AKT1 and gene amplification of AKT2 are frequently detected in ovarian cancer. Activated AKT kinases provide a cell survival signal that may confer resistance to apoptosis induced by conventional therapies in cancer cells. Therefore, development of potent inhibitors that block AKT pathway is an attractive therapeutic strategy for treating ovarian carcinoma. Methods. Ovarian cancer cell lines, A2780, MDAH2774, OVCAR-8, Caov-3, and normal murine fibroblasts (NIH3T3) were used. Cells were treated with different doses of a non-peptide small molecule compound, 9-methoxy-2-methylellipticinium acetate (termed API-59-OME) that potentially inhibit AKT pathway. Kinase assays and the phosphorylation of AKT, GSK-3α/β, PDK1, ERK1/2, SGK, p38, FAK, EGFR, JAK2, PKC isoforms, and the cleavage of poly (ADP-ribose) polymerase (PARP) were examined in treated and untreated cell lines. Further, cells treated with API-59-OME were analyzed for induction of apoptosis using sub-G1 profile with propidium iodide staining. Results. API-59-OME inhibited AKT kinase activity but did not inhibit ERK or JNK kinase activities in A2780, MDAH2774, and OVCAR-8 cell lines. API-59-OME did not reduce phosphorylation of other protein kinases in these cell lines. API-59-OME induced apoptosis and the cleavage of PARP in A2780, MDAH2774, and OVCAR-8 ovarian cancer cell lines that express elevated levels of phosphorylated AKT. In contrast, in Caov-3 and NIH3T3 cell lines, which lack constitutive AKT activity, API-59-OME only had minimal effect to induce apoptosis. Conclusion. These data suggest that API-59-OME may be a potent agent to target constitutively activated AKT pathway in ovarian cancer cells.

Original languageEnglish (US)
Pages (from-to)308-317
Number of pages10
JournalGynecologic oncology
Volume100
Issue number2
DOIs
StatePublished - Feb 1 2006

Keywords

  • AKT pathway
  • Apoptosis
  • Ovarian cancer
  • Small molecule inhibitor

ASJC Scopus subject areas

  • Oncology
  • Obstetrics and Gynecology

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  • Cite this

    Tang, H. J., Jin, X., Wang, S., Yang, D., Cao, Y., Chen, J., Gossett, D. R., & Lin, J. (2006). A small molecule compound inhibits AKT pathway in ovarian cancer cell lines. Gynecologic oncology, 100(2), 308-317. https://doi.org/10.1016/j.ygyno.2005.08.044