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

Molecular Cancer Therapeutics
Yvonne AnderssonØystein Fodstad

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 alpha-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-a...Continue Reading

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Citations

Jun 24, 2008·Journal of Drug Targeting·Xin DengGuo-Li Zhang
Aug 18, 2010·Journal of Ethnopharmacology·Yun Kai WangHao Zhu Chen
Jun 13, 2008·International Journal of Cancer. Journal International Du Cancer·Kjetil BoyeGunhild M Maelandsmo
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Feb 18, 2014·Journal of Ovarian Research·Merete Thune WiigerYvonne Andersson
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Oct 6, 2017·Oncotarget·Yvonne AnderssonKjersti Flatmark

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