Open AccessPreventing the unfolded protein response via aberrant activation of 4E‐binding protein 1 by versipelostatin
Author(s) -
Matsuo Junichi,
Tsukumo Yoshinori,
Sakurai Junko,
Tsukahara Satomi,
Park HaeRyong,
Shinya Kazuo,
Watanabe Toshiki,
Tsuruo Takashi,
Tomida Akihiro
Publication year - 2009
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/j.1349-7006.2008.01036.x
Subject(s) - atf4 , unfolded protein response , gene knockdown , transcription factor , microbiology and biotechnology , translation (biology) , integrated stress response , eukaryotic initiation factor , biology , psychological repression , apoptosis , gene expression , messenger rna , biochemistry , endoplasmic reticulum , gene
We recently isolated a macrocyclic compound, versipelostatin (VST), that exerts in vivo antitumor activity. VST shows unique, selective cytotoxicity to glucose‐deprived tumor cells by preventing the unfolded protein response (UPR). Here we show that eukaryotic initiation factor 4E‐binding protein 1 (4E‐BP1), a negative regulator of eukaryotic initiation factor 4E‐mediated protein translation, plays a role in the UPR‐inhibitory action of VST. Indeed, 4E‐BP1 is aberrantly activated by VST. This activation occurs specifically during glucose deprivation and results in profound translation repression and prevents induction of the typical UPR markers glucose‐regulated protein (GRP) 78 and activating transcription factor (ATF) 4. Our overexpression and knockdown experiments showed that 4E‐BP1 can regulate GRP78 and ATF4 expression. These mechanisms appear to be specific for VST. By contrast, rapamycin, which activates 4E‐BP1 regardless of cellular glucose availability, has only marginal effects on the expression of GRP78 and ATF4. Our present findings demonstrate that aberrant 4E‐BP1 activation can contribute to UPR preventing by VST, possibly through a mechanism that does not operate in rapamycin‐treated cells. ( Cancer Sci 2009; 100: 327–333)