Plant ribosome-inactivating proteins type II induce the unfolded protein response in human cancer cells.
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.
Horrix
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Toxicology and Chemotherapy Unit, German Cancer Research Center, Im Neuenheimer Feld 581, 69120, Heidelberg, Germany. c.horrix@dkfz.de
Raviv
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Z
Flescher
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Voss
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Berger
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MR
D051702:Activating Transcription Factor 6 / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor / Q000502:physiology*; D004721:Endoplasmic Reticulum / Q000378:metabolism; D004722:Endoribonucleases / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D046228:Microarray Analysis; D010940:Plant Proteins / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D012339:RNA, Ribosomal, 28S / Q000235:genetics / Q000378:metabolism; D054790:Ribosome Inactivating Proteins, Type 2 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D056811:Unfolded Protein Response / Q000502:physiology*; D019892:eIF-2 Kinase / Q000235:genetics / Q000378:metabolism
D051702:Activating Transcription Factor 6; D004722:Endoribonucleases; D008565:Membrane Proteins; D010940:Plant Proteins; D017346:Protein Serine-Threonine Kinases; D012339:RNA, Ribosomal, 28S; D054790:Ribosome Inactivating Proteins, Type 2; D019892:eIF-2 Kinase; C403982:ERN2 protein, human