The synthetic oleanane triterpenoid CDDO‐2P‐Im binds GRP78/BiP to induce unfolded protein response‐mediated apoptosis in myeloma
Synthetic oleanane triterpenoids (SOTs) are small molecules with broad anticancer properties. A recently developed SOT, 1‐[2‐cyano‐3,12‐dioxooleana‐1,9(11)‐dien‐28‐oyl]‐4(‐pyridin‐2‐yl)‐1H‐imidazole (CDDO‐2P‐Im or ‘2P‐Im’), exhibits enhanced activity and improved pharmacokinetics over CDDO‐Im, a pre...
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| Published in: | Molecular oncology Vol. 17; no. 12; pp. 2526 - 2545 |
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| Main Authors: | , , , , , , , , , , |
| Format: | Journal Article |
| Language: | English |
| Published: |
United States
John Wiley & Sons, Inc
01-12-2023
Wiley |
| Subjects: | |
| Online Access: | Get full text |
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| Summary: | Synthetic oleanane triterpenoids (SOTs) are small molecules with broad anticancer properties. A recently developed SOT, 1‐[2‐cyano‐3,12‐dioxooleana‐1,9(11)‐dien‐28‐oyl]‐4(‐pyridin‐2‐yl)‐1H‐imidazole (CDDO‐2P‐Im or ‘2P‐Im’), exhibits enhanced activity and improved pharmacokinetics over CDDO‐Im, a previous generation SOT. However, the mechanisms leading to these properties are not defined. Here, we show the synergy of 2P‐Im and the proteasome inhibitor ixazomib in human multiple myeloma (MM) cells and 2P‐Im activity in a murine model of plasmacytoma. RNA sequencing and quantitative reverse transcription PCR revealed the upregulation of the unfolded protein response (UPR) in MM cells upon 2P‐lm treatment, implicating the activation of the UPR as a key step in 2P‐Im‐induced apoptosis. Supporting this hypothesis, the deletion of genes encoding either protein kinase R‐like endoplasmic reticulum kinase (PERK) or DNA damage‐inducible transcript 3 protein (DDIT3; also known as CHOP) impaired the MM response to 2P‐Im, as did treatment with ISRIB, integrated stress response inhibitor, which inhibits UPR signaling downstream of PERK. Finally, both drug affinity responsive target stability and thermal shift assays demonstrated direct binding of 2P‐Im to endoplasmic reticulum chaperone BiP (GRP78/BiP), a stress‐inducible key signaling molecule of the UPR. These data reveal GRP78/BiP as a novel target of SOTs, and specifically of 2P‐Im, and suggest the potential broader utility of this class of small molecules as modulators of the UPR.
The synthetic oleanane triterpenoid CDDO‐2P‐Im selectively interacts with specific protein targets in a concentration‐dependent manner. At low concentrations, its binding to KEAP1 leads to the activation of Nrf2 target gene expression. As the concentration of CDDO‐2P‐Im increases, it binds to GRP78, leading to the activation of the unfolded protein response and the upregulation of ATF4 and XBP1 target genes. |
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| Bibliography: | In memoriam: We would like to pay tribute to our dear mentor, colleague, and friend, Dr. Michael B. Sporn, who passed away unexpectedly during the completion of this manuscript. Dr. Sporn was not only the inspiration behind this work, but he also provided the vision behind the development of the entire class of synthetic oleanane triterpenoids. He never lost his drive and motivation to see these agents advance to the clinic to benefit cancer patients. He was the founder of Triterpenoid Therapuetics, Inc., an entity that carries on this effort in his legacy. Dr. Sporn was a remarkable physician‐scientist and innovator whose actions and efforts have spawned a generation of scientists around the globe. He will be greatly missed. https://www.nature.com/articles/548S16a ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
| ISSN: | 1574-7891 1878-0261 |
| DOI: | 10.1002/1878-0261.13447 |