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

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

Research output: Contribution to journalArticle

38 Scopus citations

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 (US)
Pages (from-to)1171-1179
Number of pages9
JournalJournal of Cellular Biochemistry
Volume102
Issue number5
DOIs
StatePublished - Dec 1 2007

Keywords

  • AKT
  • BCL-2
  • Pancreatic cancer

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology

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