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...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2023-12-01
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| Series: | Molecular Oncology |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/1878-0261.13447 |
| _version_ | 1827593419517591552 |
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| author | George Luo Kristin Aldridge Toby Chen Vivek Aslot Byung‐Gyu Kim Eun Hyang Han Neelima Singh Sai Li Tsan Sam Xiao Michael B. Sporn John J. Letterio |
| author_facet | George Luo Kristin Aldridge Toby Chen Vivek Aslot Byung‐Gyu Kim Eun Hyang Han Neelima Singh Sai Li Tsan Sam Xiao Michael B. Sporn John J. Letterio |
| author_sort | George Luo |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-09T02:11:15Z |
| format | Article |
| id | doaj.art-ea461143de2240b5ab41bd51465ba88f |
| institution | Directory Open Access Journal |
| issn | 1574-7891 1878-0261 |
| language | English |
| last_indexed | 2024-03-09T02:11:15Z |
| publishDate | 2023-12-01 |
| publisher | Wiley |
| record_format | Article |
| series | Molecular Oncology |
| spelling | doaj.art-ea461143de2240b5ab41bd51465ba88f2023-12-07T11:50:08ZengWileyMolecular Oncology1574-78911878-02612023-12-0117122526254510.1002/1878-0261.13447The synthetic oleanane triterpenoid CDDO‐2P‐Im binds GRP78/BiP to induce unfolded protein response‐mediated apoptosis in myelomaGeorge Luo0Kristin Aldridge1Toby Chen2Vivek Aslot3Byung‐Gyu Kim4Eun Hyang Han5Neelima Singh6Sai Li7Tsan Sam Xiao8Michael B. Sporn9John J. Letterio10Department of Pathology Case Western Reserve University School of Medicine Cleveland OH USATriterpenoid Therapeutics Inc. Tunbridge VT USATrinity College of Arts and Sciences Duke University Durham NC USADepartment of Chemical and Biomolecular Engineering Case Western Reserve University Cleveland OH USAThe Angie Fowler Adolescent and Young Adult Cancer Institute University Hospitals Rainbow Babies & Children's Hospital Cleveland OH USAThe Angie Fowler Adolescent and Young Adult Cancer Institute University Hospitals Rainbow Babies & Children's Hospital Cleveland OH USAThe Angie Fowler Adolescent and Young Adult Cancer Institute University Hospitals Rainbow Babies & Children's Hospital Cleveland OH USADepartment of Pathology Case Western Reserve University School of Medicine Cleveland OH USADepartment of Pathology Case Western Reserve University School of Medicine Cleveland OH USATriterpenoid Therapeutics Inc. Tunbridge VT USAThe Angie Fowler Adolescent and Young Adult Cancer Institute University Hospitals Rainbow Babies & Children's Hospital Cleveland OH USASynthetic 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.https://doi.org/10.1002/1878-0261.13447apoptosisCDDO‐2P‐ImGRP78myelomatriterpenoidUPR |
| spellingShingle | George Luo Kristin Aldridge Toby Chen Vivek Aslot Byung‐Gyu Kim Eun Hyang Han Neelima Singh Sai Li Tsan Sam Xiao Michael B. Sporn John J. Letterio The synthetic oleanane triterpenoid CDDO‐2P‐Im binds GRP78/BiP to induce unfolded protein response‐mediated apoptosis in myeloma Molecular Oncology apoptosis CDDO‐2P‐Im GRP78 myeloma triterpenoid UPR |
| title | The synthetic oleanane triterpenoid CDDO‐2P‐Im binds GRP78/BiP to induce unfolded protein response‐mediated apoptosis in myeloma |
| title_full | The synthetic oleanane triterpenoid CDDO‐2P‐Im binds GRP78/BiP to induce unfolded protein response‐mediated apoptosis in myeloma |
| title_fullStr | The synthetic oleanane triterpenoid CDDO‐2P‐Im binds GRP78/BiP to induce unfolded protein response‐mediated apoptosis in myeloma |
| title_full_unstemmed | The synthetic oleanane triterpenoid CDDO‐2P‐Im binds GRP78/BiP to induce unfolded protein response‐mediated apoptosis in myeloma |
| title_short | The synthetic oleanane triterpenoid CDDO‐2P‐Im binds GRP78/BiP to induce unfolded protein response‐mediated apoptosis in myeloma |
| title_sort | synthetic oleanane triterpenoid cddo 2p im binds grp78 bip to induce unfolded protein response mediated apoptosis in myeloma |
| topic | apoptosis CDDO‐2P‐Im GRP78 myeloma triterpenoid UPR |
| url | https://doi.org/10.1002/1878-0261.13447 |
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