BCL-2 functions as an activator of the AKT signaling pathway in pancreatic cancer

Melinda M. Mortenson, Joseph G. Galante, Oren Gilad, Michael G. Schlieman, Subbulakshmi Virudachalam, Hsing Jien Kung, Richard J. Bold

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38 Citations (Scopus)

Abstract

BCL-2 is the prototypic anti-apoptotic protein involved in the regulation of apoptosis. Overexpression of BCL-2 is common in pancreatic cancer and confers resistance to the apoptotic effect of chemo- and radiotherapy. Although these cellular effects of BCL-2 are traditionally related to pathways involving the mitochondrial membrane, we sought to investigate whether BCL-2 is involved in other signaling pathways regulating cell survival and focused on AKT. We examined the effect of overexpression of BCL-2 in the MIA-PaCa-2 human pancreatic cancer cell line on the function and subcellular location of AKT. We observed that the stable subclones of MIA-PaCa-2 overexpressing BCL-2 demonstrated increased activity of AKT as well as IKK (a downstream target of AKT), increasing the transcriptional activity of NF-κB. Using immunoprecipitation techniques, we observed co-immunoprecipitation of AKT and BCL-2. Immunocytochemistry demonstrated co-localization of BCL-2 and AKT, which was abrogated by treatment with HA14-1, a small molecule inhibitor of BH-3-mediated protein interaction by BCL-2. Furthermore, treatment with HA14-1 decreased phosphorylation of AKT and increased sensitivity to the apoptotic effect of the chemotherapeutic agent, paclitaxel. These results demonstrate an additional mechanism of regulation of cell survival mediated by BCL-2, namely through AKT activation, in the MIA-PaCa-2 pancreatic cancer cell line. Therefore, directed inhibition of BCL-2 may alter diverse pathways controlling cell survival and overcome the apoptotic resistance that is the hallmark of pancreatic cancer.

Original languageEnglish
Pages (from-to)1171-1179
Number of pages9
JournalJournal of Cellular Biochemistry
Volume102
Issue number5
DOIs
Publication statusPublished - Dec 1 2007
Externally publishedYes

Keywords

  • AKT
  • BCL-2
  • Pancreatic cancer

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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  • Cite this

    Mortenson, M. M., Galante, J. G., Gilad, O., Schlieman, M. G., Virudachalam, S., Kung, H. J., & Bold, R. J. (2007). BCL-2 functions as an activator of the AKT signaling pathway in pancreatic cancer. Journal of Cellular Biochemistry, 102(5), 1171-1179. https://doi.org/10.1002/jcb.21343