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Research Articles: Therapeutics

AMP-activated protein kinase protects against anti–epidermal growth factor receptor-Pseudomonas exotoxin A immunotoxin-induced MA11 breast cancer cell death

Department of Tumor Biology and Institute for Cancer Research, Norwegian Radium Hospital, Oslo, Norway

Requests for reprints: Yvonne Andersson, Department of Tumor Biology and Institute for Cancer Research, Norwegian Radium Hospital, 0310 Oslo, Norway. Phone: 47-22935421; Fax: 47-22522421. E-mail: y.g.andersson{at}medisin.uio.no

Abstract

We have shown previously that our 425.3PE immunotoxin inhibits protein synthesis and induces apoptosis in human breast cancer cells. In attempts to further elucidate the intracellular pathways implicated in its cellular effects, we found that the immunotoxin induced an initial stress response, which rapidly caused an imbalance in the cellular energy status with an increase in reactive oxygen species. The AMP-activated protein kinase (AMPK), a sensor of increased cellular AMP/ATP ratio, was activated by 425.3PE. An immunotoxin-induced activation of c-Jun NH₂-terminal kinase (JNK) preceded and overlapped caspase-mediated cleavage of the -subunit of AMPK in a time- and dose-dependent manner. The JNK activation occurred already at a dose level too low to induce any detectable changes in the apoptotic machinery or protein synthesis. In contrast, cycloheximide, even at a concentration causing a 90% inhibition of protein synthesis, did neither affect the ATP level nor activate JNK and AMPK. Pretreatment of the cells with the specific AMPK inhibitor compound C and JNK inhibitor SP600125 blocked activation of AMPK and JNK, respectively, and subsequently sensitized the cells to 425.3PE-induced cell death. Whereas the antioxidant N-acetyl-L-cysteine blocked the generation of reactive oxygen species and activation of JNK and AMPK, it did not block immunotoxin-induced apoptosis. Together, the results show that 425.3PE induces several parallel signaling events, observed initially as an early activation of survival pathways, protecting the cells against the toxic effects of the immunotoxin, followed by subsequent apoptosis induction and protein synthesis inhibition. Conceivably, therapeutic manipulation of the signaling intermediates AMPK and JNK might provide a means to maximize the anticancer effects of the 425.3 immunotoxin. [Mol Cancer Ther 2006;5(4):1050–9]

Grant support: Norwegian Cancer Society and the Norwegian Radium Hospital.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: The current address for Ø. Fodstad is Cancer Research Institute, University of South Alabama, Mobile, AL 36688.

Received 8/12/05; revised 11/14/05; accepted 1/ 5/06.

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