Importance of Cullin4 Ubiquitin Ligase in Malignant Pleural Mesothelioma
Neurofibromatosis type 2 (NF2), the tumor suppressor frequently lost in malignant pleural mesothelioma (MPM), suppresses tumorigenesis in part by inhibiting the Cullin4 ubiquitin ligase (CUL4) complex in the nucleus. Here, we evaluated the importance of CUL4 in MPM progression and tested the efficac...
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| Veröffentlicht in: | Cancers 2020-11, Vol.12 (11), p.3460 |
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| creator | Meerang, Mayura Kreienbühl, Jessica Orlowski, Vanessa Müller, Seraina L. C. Kirschner, Michaela B. Opitz, Isabelle |
| description | Neurofibromatosis type 2 (NF2), the tumor suppressor frequently lost in malignant pleural mesothelioma (MPM), suppresses tumorigenesis in part by inhibiting the Cullin4 ubiquitin ligase (CUL4) complex in the nucleus. Here, we evaluated the importance of CUL4 in MPM progression and tested the efficacy of cullin inhibition by pevonedistat, a small molecule inhibiting cullin neddylation. CUL4 paralogs (CUL4A and CUL4B) were upregulated in MPM tumor specimens compared to nonmalignant pleural tissues. High gene and protein expressions of CUL4B was associated with a worse progression-free survival of MPM patients. Among 13 MPM cell lines tested, five (38%) were highly sensitive to pevonedistat (half maximal inhibitory concentration of cell survival IC50 < 0.5 µM). This remained true in a 3D spheroid culture. Pevonedistat treatment caused the accumulation of CDT1 and p21 in both sensitive and resistant cell lines. However, the treatment induced S/G2 cell cycle arrest and DNA rereplication predominantly in the sensitive cell lines. In an in vivo mouse model, the pevonedistat treatment significantly prolonged the survival of mice bearing both sensitive and resistant MPM tumors. Pevonedistat treatment reduced growth in sensitive tumors but increased apoptosis in resistant tumors. The mechanism in the resistant tumor model may be mediated by reduced macrophage infiltration, resulting from the suppression of macrophage chemotactic cytokines, C-C motif chemokine ligand 2 (CCL2), expression in tumor cells. |
| doi_str_mv | 10.3390/cancers12113460 |
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C. ; Kirschner, Michaela B. ; Opitz, Isabelle</creator><creatorcontrib>Meerang, Mayura ; Kreienbühl, Jessica ; Orlowski, Vanessa ; Müller, Seraina L. C. ; Kirschner, Michaela B. ; Opitz, Isabelle</creatorcontrib><description>Neurofibromatosis type 2 (NF2), the tumor suppressor frequently lost in malignant pleural mesothelioma (MPM), suppresses tumorigenesis in part by inhibiting the Cullin4 ubiquitin ligase (CUL4) complex in the nucleus. Here, we evaluated the importance of CUL4 in MPM progression and tested the efficacy of cullin inhibition by pevonedistat, a small molecule inhibiting cullin neddylation. CUL4 paralogs (CUL4A and CUL4B) were upregulated in MPM tumor specimens compared to nonmalignant pleural tissues. High gene and protein expressions of CUL4B was associated with a worse progression-free survival of MPM patients. Among 13 MPM cell lines tested, five (38%) were highly sensitive to pevonedistat (half maximal inhibitory concentration of cell survival IC50 < 0.5 µM). This remained true in a 3D spheroid culture. Pevonedistat treatment caused the accumulation of CDT1 and p21 in both sensitive and resistant cell lines. However, the treatment induced S/G2 cell cycle arrest and DNA rereplication predominantly in the sensitive cell lines. In an in vivo mouse model, the pevonedistat treatment significantly prolonged the survival of mice bearing both sensitive and resistant MPM tumors. Pevonedistat treatment reduced growth in sensitive tumors but increased apoptosis in resistant tumors. The mechanism in the resistant tumor model may be mediated by reduced macrophage infiltration, resulting from the suppression of macrophage chemotactic cytokines, C-C motif chemokine ligand 2 (CCL2), expression in tumor cells.</description><identifier>ISSN: 2072-6694</identifier><identifier>EISSN: 2072-6694</identifier><identifier>DOI: 10.3390/cancers12113460</identifier><identifier>PMID: 33233664</identifier><language>eng</language><publisher>Basel: MDPI AG</publisher><subject>Apoptosis ; Cancer ; Cell culture ; Cell cycle ; Cell survival ; Chemokines ; Chemotherapy ; Clinical trials ; Cullin ; Cyclin-dependent kinases ; Cytokines ; Deoxyribonucleic acid ; DNA ; Enzymes ; Gene expression ; Health aspects ; Kinases ; Ligases ; Macrophages ; Mesothelioma ; Metastases ; Monocyte chemoattractant protein 1 ; Neurofibromatosis ; Neurofibromatosis 2 ; Neurofibromin 2 ; Patients ; Physiological aspects ; Protein expression ; Proteins ; Tumor cells ; Tumor suppressor genes ; Tumorigenesis ; Tumors ; Ubiquitin ; Ubiquitin-protein ligase</subject><ispartof>Cancers, 2020-11, Vol.12 (11), p.3460</ispartof><rights>COPYRIGHT 2020 MDPI AG</rights><rights>2020. This work is licensed under http://creativecommons.org/licenses/by/3.0/ (the “License”). 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C.</creatorcontrib><creatorcontrib>Kirschner, Michaela B.</creatorcontrib><creatorcontrib>Opitz, Isabelle</creatorcontrib><title>Importance of Cullin4 Ubiquitin Ligase in Malignant Pleural Mesothelioma</title><title>Cancers</title><description>Neurofibromatosis type 2 (NF2), the tumor suppressor frequently lost in malignant pleural mesothelioma (MPM), suppresses tumorigenesis in part by inhibiting the Cullin4 ubiquitin ligase (CUL4) complex in the nucleus. Here, we evaluated the importance of CUL4 in MPM progression and tested the efficacy of cullin inhibition by pevonedistat, a small molecule inhibiting cullin neddylation. CUL4 paralogs (CUL4A and CUL4B) were upregulated in MPM tumor specimens compared to nonmalignant pleural tissues. High gene and protein expressions of CUL4B was associated with a worse progression-free survival of MPM patients. Among 13 MPM cell lines tested, five (38%) were highly sensitive to pevonedistat (half maximal inhibitory concentration of cell survival IC50 < 0.5 µM). This remained true in a 3D spheroid culture. Pevonedistat treatment caused the accumulation of CDT1 and p21 in both sensitive and resistant cell lines. However, the treatment induced S/G2 cell cycle arrest and DNA rereplication predominantly in the sensitive cell lines. In an in vivo mouse model, the pevonedistat treatment significantly prolonged the survival of mice bearing both sensitive and resistant MPM tumors. Pevonedistat treatment reduced growth in sensitive tumors but increased apoptosis in resistant tumors. The mechanism in the resistant tumor model may be mediated by reduced macrophage infiltration, resulting from the suppression of macrophage chemotactic cytokines, C-C motif chemokine ligand 2 (CCL2), expression in tumor cells.</description><subject>Apoptosis</subject><subject>Cancer</subject><subject>Cell culture</subject><subject>Cell cycle</subject><subject>Cell survival</subject><subject>Chemokines</subject><subject>Chemotherapy</subject><subject>Clinical trials</subject><subject>Cullin</subject><subject>Cyclin-dependent kinases</subject><subject>Cytokines</subject><subject>Deoxyribonucleic acid</subject><subject>DNA</subject><subject>Enzymes</subject><subject>Gene expression</subject><subject>Health aspects</subject><subject>Kinases</subject><subject>Ligases</subject><subject>Macrophages</subject><subject>Mesothelioma</subject><subject>Metastases</subject><subject>Monocyte chemoattractant protein 1</subject><subject>Neurofibromatosis</subject><subject>Neurofibromatosis 2</subject><subject>Neurofibromin 2</subject><subject>Patients</subject><subject>Physiological aspects</subject><subject>Protein expression</subject><subject>Proteins</subject><subject>Tumor cells</subject><subject>Tumor suppressor genes</subject><subject>Tumorigenesis</subject><subject>Tumors</subject><subject>Ubiquitin</subject><subject>Ubiquitin-protein ligase</subject><issn>2072-6694</issn><issn>2072-6694</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>8G5</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNpdkUtPAyEURonRqKmu3U7ixk0tr4GZjYlp1Dap0YWuCYN3WgwDFWZM_PdSa3yUDR9wcu4lF6Ezgi8Zq_HEaG8gJkIJYVzgPXRMsaRjIWq-_ycfodOUXnFejBEp5CE6YowyJgQ_RrN5tw6x35iK0BbTwTnrefHc2LfB9tYXC7vUCYqc7rWzS699Xzw6GKJ2xT2k0K_A2dDpE3TQapfg9Hsfoefbm6fpbLx4uJtPrxdjw6nox21Z6kZWtOXAMOcNxgB1U2lSSVqxUlb5LA2hDc6XhpcGV43MARMw-kVTNkJXW-96aDp4MeD73IpaR9vp-KGCtur_i7crtQzvSoq6lhRnwcW3IIa3AVKvOpsMOKc9hCEpygUnNSuxyOj5Dvoahujz974oSmrJql9qqR0o69uQ65qNVF0LXmKamTpTky1lYkgpQvvTMsFqM061M072CQO0kaI</recordid><startdate>20201120</startdate><enddate>20201120</enddate><creator>Meerang, Mayura</creator><creator>Kreienbühl, Jessica</creator><creator>Orlowski, Vanessa</creator><creator>Müller, Seraina L. 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C.</au><au>Kirschner, Michaela B.</au><au>Opitz, Isabelle</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Importance of Cullin4 Ubiquitin Ligase in Malignant Pleural Mesothelioma</atitle><jtitle>Cancers</jtitle><date>2020-11-20</date><risdate>2020</risdate><volume>12</volume><issue>11</issue><spage>3460</spage><pages>3460-</pages><issn>2072-6694</issn><eissn>2072-6694</eissn><abstract>Neurofibromatosis type 2 (NF2), the tumor suppressor frequently lost in malignant pleural mesothelioma (MPM), suppresses tumorigenesis in part by inhibiting the Cullin4 ubiquitin ligase (CUL4) complex in the nucleus. Here, we evaluated the importance of CUL4 in MPM progression and tested the efficacy of cullin inhibition by pevonedistat, a small molecule inhibiting cullin neddylation. CUL4 paralogs (CUL4A and CUL4B) were upregulated in MPM tumor specimens compared to nonmalignant pleural tissues. High gene and protein expressions of CUL4B was associated with a worse progression-free survival of MPM patients. Among 13 MPM cell lines tested, five (38%) were highly sensitive to pevonedistat (half maximal inhibitory concentration of cell survival IC50 < 0.5 µM). This remained true in a 3D spheroid culture. Pevonedistat treatment caused the accumulation of CDT1 and p21 in both sensitive and resistant cell lines. However, the treatment induced S/G2 cell cycle arrest and DNA rereplication predominantly in the sensitive cell lines. In an in vivo mouse model, the pevonedistat treatment significantly prolonged the survival of mice bearing both sensitive and resistant MPM tumors. Pevonedistat treatment reduced growth in sensitive tumors but increased apoptosis in resistant tumors. The mechanism in the resistant tumor model may be mediated by reduced macrophage infiltration, resulting from the suppression of macrophage chemotactic cytokines, C-C motif chemokine ligand 2 (CCL2), expression in tumor cells.</abstract><cop>Basel</cop><pub>MDPI AG</pub><pmid>33233664</pmid><doi>10.3390/cancers12113460</doi><orcidid>https://orcid.org/0000-0001-5900-9040</orcidid><orcidid>https://orcid.org/0000-0001-7444-9829</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Apoptosis Cancer Cell culture Cell cycle Cell survival Chemokines Chemotherapy Clinical trials Cullin Cyclin-dependent kinases Cytokines Deoxyribonucleic acid DNA Enzymes Gene expression Health aspects Kinases Ligases Macrophages Mesothelioma Metastases Monocyte chemoattractant protein 1 Neurofibromatosis Neurofibromatosis 2 Neurofibromin 2 Patients Physiological aspects Protein expression Proteins Tumor cells Tumor suppressor genes Tumorigenesis Tumors Ubiquitin Ubiquitin-protein ligase |
| title | Importance of Cullin4 Ubiquitin Ligase in Malignant Pleural Mesothelioma |
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