DNAJA1- and conformational mutant p53-dependent inhibition of cancer cell migration by a novel compound identified through a virtual screen
Abstract Cancers are frequently addicted to oncogenic missense mutant p53 (mutp53). DNAJA1, a member of heat shock protein 40 (HSP40), also known as J-domain proteins (JDPs), plays a crucial role in the stabilization and oncogenic activity of misfolded or conformational mutp53 by binding to and prev...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2022-10-01
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| Series: | Cell Death Discovery |
| Online Access: | https://doi.org/10.1038/s41420-022-01229-5 |
| _version_ | 1828201088222756864 |
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| author | Shigeto Nishikawa Atsushi Kaida Alejandro Parrales Atul Ranjan Mohamed Alalem Hongyi Ren Frank J. Schoenen David K. Johnson Tomoo Iwakuma |
| author_facet | Shigeto Nishikawa Atsushi Kaida Alejandro Parrales Atul Ranjan Mohamed Alalem Hongyi Ren Frank J. Schoenen David K. Johnson Tomoo Iwakuma |
| author_sort | Shigeto Nishikawa |
| collection | DOAJ |
| description | Abstract Cancers are frequently addicted to oncogenic missense mutant p53 (mutp53). DNAJA1, a member of heat shock protein 40 (HSP40), also known as J-domain proteins (JDPs), plays a crucial role in the stabilization and oncogenic activity of misfolded or conformational mutp53 by binding to and preventing mutp53 from proteasomal degradation. However, strategies to deplete mutp53 are not well-established, and no HSP40/JDPs inhibitors are clinically available. To identify compounds that bind to DNAJA1 and induce mutp53 degradation, we performed an in silico docking study of ~10 million of compounds from the ZINC database for the J-domain of DNAJA1. A compound 7-3 was identified, and its analogue A11 effectively reduced the levels of DNAJA1 and conformational mutp53 with minimal effects on the levels of wild-type p53 and DNA-contact mutp53. A11 suppressed migration and filopodia formation in a manner dependent on DNAJA1 and conformational mutp53. A mutant DNAJA1 with alanine mutations at predicted amino acids (tyrosine 7, lysine 44, and glutamine 47) failed to bind to A11. Cells expressing the mutant DNAJA1 became insensitive to A11-mediated depletion of DNAJA1 and mutp53 as well as A11-mediated inhibition of cell migration. Thus, A11 is the first HSP40/JDP inhibitor that has not been previously characterized for depleting DNAJA1 and subsequently conformational mutp53, leading to inhibition of cancer cell migration. A11 can be exploited for a novel treatment against cancers expressing conformational mutp53. |
| first_indexed | 2024-04-12T11:24:04Z |
| format | Article |
| id | doaj.art-32dc6a9804484bb98536de5316509fc1 |
| institution | Directory Open Access Journal |
| issn | 2058-7716 |
| language | English |
| last_indexed | 2024-04-12T11:24:04Z |
| publishDate | 2022-10-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death Discovery |
| spelling | doaj.art-32dc6a9804484bb98536de5316509fc12022-12-22T03:35:16ZengNature Publishing GroupCell Death Discovery2058-77162022-10-018111810.1038/s41420-022-01229-5DNAJA1- and conformational mutant p53-dependent inhibition of cancer cell migration by a novel compound identified through a virtual screenShigeto Nishikawa0Atsushi Kaida1Alejandro Parrales2Atul Ranjan3Mohamed Alalem4Hongyi Ren5Frank J. Schoenen6David K. Johnson7Tomoo Iwakuma8Department of Pediatrics, Division of Hematology & Oncology, Children’s Mercy Research InstituteDepartment of Dental Radiology and Radiation Oncology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental UniversityDepartment of Pediatrics, Division of Hematology & Oncology, Children’s Mercy Research InstituteDepartment of Pediatrics, Division of Hematology & Oncology, Children’s Mercy Research InstituteDepartment of Pediatrics, Division of Hematology & Oncology, Children’s Mercy Research InstituteDepartment of Cancer Biology, University of Kansas Medical CenterHiguchi Biosciences Center, University of KansasMolecular Graphics and Modeling Laboratory, University of KansasDepartment of Pediatrics, Division of Hematology & Oncology, Children’s Mercy Research InstituteAbstract Cancers are frequently addicted to oncogenic missense mutant p53 (mutp53). DNAJA1, a member of heat shock protein 40 (HSP40), also known as J-domain proteins (JDPs), plays a crucial role in the stabilization and oncogenic activity of misfolded or conformational mutp53 by binding to and preventing mutp53 from proteasomal degradation. However, strategies to deplete mutp53 are not well-established, and no HSP40/JDPs inhibitors are clinically available. To identify compounds that bind to DNAJA1 and induce mutp53 degradation, we performed an in silico docking study of ~10 million of compounds from the ZINC database for the J-domain of DNAJA1. A compound 7-3 was identified, and its analogue A11 effectively reduced the levels of DNAJA1 and conformational mutp53 with minimal effects on the levels of wild-type p53 and DNA-contact mutp53. A11 suppressed migration and filopodia formation in a manner dependent on DNAJA1 and conformational mutp53. A mutant DNAJA1 with alanine mutations at predicted amino acids (tyrosine 7, lysine 44, and glutamine 47) failed to bind to A11. Cells expressing the mutant DNAJA1 became insensitive to A11-mediated depletion of DNAJA1 and mutp53 as well as A11-mediated inhibition of cell migration. Thus, A11 is the first HSP40/JDP inhibitor that has not been previously characterized for depleting DNAJA1 and subsequently conformational mutp53, leading to inhibition of cancer cell migration. A11 can be exploited for a novel treatment against cancers expressing conformational mutp53.https://doi.org/10.1038/s41420-022-01229-5 |
| spellingShingle | Shigeto Nishikawa Atsushi Kaida Alejandro Parrales Atul Ranjan Mohamed Alalem Hongyi Ren Frank J. Schoenen David K. Johnson Tomoo Iwakuma DNAJA1- and conformational mutant p53-dependent inhibition of cancer cell migration by a novel compound identified through a virtual screen Cell Death Discovery |
| title | DNAJA1- and conformational mutant p53-dependent inhibition of cancer cell migration by a novel compound identified through a virtual screen |
| title_full | DNAJA1- and conformational mutant p53-dependent inhibition of cancer cell migration by a novel compound identified through a virtual screen |
| title_fullStr | DNAJA1- and conformational mutant p53-dependent inhibition of cancer cell migration by a novel compound identified through a virtual screen |
| title_full_unstemmed | DNAJA1- and conformational mutant p53-dependent inhibition of cancer cell migration by a novel compound identified through a virtual screen |
| title_short | DNAJA1- and conformational mutant p53-dependent inhibition of cancer cell migration by a novel compound identified through a virtual screen |
| title_sort | dnaja1 and conformational mutant p53 dependent inhibition of cancer cell migration by a novel compound identified through a virtual screen |
| url | https://doi.org/10.1038/s41420-022-01229-5 |
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