Plant ribosome-inactivating proteins type II induce the unfolded protein response in human cancer cells |
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Authors: | C Horrix Z Raviv E Flescher C Voss M R Berger |
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Institution: | (1) Toxicology and Chemotherapy Unit, German Cancer Research Center, Im Neuenheimer Feld 581, 69120 Heidelberg, Germany;(2) Department of Clinical Microbiology and Immunology, Sackler School of Medicine, Tel-Aviv University, Ramat Aviv, 69978 Tel Aviv, Israel;(3) Department of Biochemistry, Heidelberg Pharma AG, Schriesheimer Strasse 101, 68526 Ladenburg, Germany |
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Abstract: | Cytotoxic ribosome-inactivating proteins (RIPs) of type II such as ricin were investigated as anti-cancer agents, but also
pose a threat as biological weapons. The molecular mechanism leading to their toxic effects is, however, not yet clear. The
current paradigm, which states that the irreversible depurination of 28S rRNA results in a general translational arrest eventually
leading to cell death, has been questioned. Using micro-array, qRT-PCR and Western blot, we identified the unfolded protein
response (UPR), a cellular mechanism activated in response to endoplasmic reticulum stress, that is induced in HCT116 and
MDA-MB-231 cells exposed to the plant type II RIPs ricin, riproximin and volkensin. Apoptosis was induced by concentrations
at which translation of UPR-related genes still occurred, despite concomitant ribosomal depurination. We conclude that UPR
induction represents a model that better describes the cellular effects of RIP exposure at concentrations at which selected
proteins are translated despite ribosomal depurination. |
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