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Selective, potent blockade of the IRE 1 and ATF 6 pathways by 4‐phenylbutyric acid analogues
Author(s) -
Zhang Hui,
Nakajima Shotaro,
Kato Hironori,
Gu Liubao,
Yoshitomi Tatsuya,
Nagai Kaoru,
Shinmori Hideyuki,
Kokubo Susumu,
Kitamura Masanori
Publication year - 2013
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.12306
Subject(s) - unfolded protein response , tunicamycin , endoplasmic reticulum , thapsigargin , phosphorylation , chemical chaperone , phenylbutyrate , chemistry , microbiology and biotechnology , pharmacology , biochemistry , biology , endocrinology
Background and Purpose 4‐Phenylbutyric acid (4‐ PBA ) is a chemical chaperone that eliminates the accumulation of unfolded proteins in the endoplasmic reticulum ( ER ). However, its chaperoning ability is often weak and unable to attenuate the unfolded protein response ( UPR ) in vitro or in vivo . To develop more potent chemical chaperones, we synthesized six analogues of 4‐ PBA and evaluated their pharmacological actions on the UPR . Experimental Approach NRK ‐52E cells were treated with ER stress inducers (tunicamycin or thapsigargin) in the presence of each of the 4‐ PBA analogues; the suppressive effects of these analogues on the UPR were assessed using selective indicators for individual UPR pathways. Key Results 2‐ POAA ‐ OMe , 2‐ POAA ‐ NO 2 and 2‐ NOAA , but not others, suppressed the induction of ER stress markers GRP 78 and CHOP . This suppressive effect was more potent than that of 4‐ PBA . Of the three major UPR branches, the IRE 1 and ATF 6 pathways were markedly blocked by these compounds, as indicated by suppression of XBP 1 splicing, inhibition of UPRE and ERSE activation, and inhibition of JNK phosphorylation. Unexpectedly, however, these agents did not inhibit phosphorylation of PERK and e IF 2α triggered by ER stress. These compounds dose‐dependently inhibited the early activation of NF ‐κ B in ER stress‐exposed cells. 2‐ POAA ‐ OMe and 2‐ POAA ‐ NO 2 also inhibited ER stress‐induced phosphorylation of A kt. Conclusion and Implications The 4‐ PBA analogues 2‐POAA‐OMe, 2‐POAA‐NO 2 and 2‐NOAA strongly inhibited activation of the IRE 1 and ATF 6 pathways and downstream pathogenic targets, including NF ‐κ B and A kt, in ER stress‐exposed cells. These compounds may be useful for therapeutic intervention in ER stress‐related pathological conditions.