Targeting MDM4 as a Novel Therapeutic Approach in Prostate Cancer Independent of p53 Status
Metastatic prostate cancer is a lethal disease in patients incapable of responding to therapeutic interventions. Invasive prostate cancer spread is caused by failure of the normal anti-cancer defense systems that are controlled by the tumour suppressor protein, p53. Upon mutation, p53 malfunctions....
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-08-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/14/16/3947 |
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| author | Javier Octavio Mejía-Hernández Dinesh Raghu Franco Caramia Nicholas Clemons Kenji Fujihara Thomas Riseborough Amina Teunisse Aart G. Jochemsen Lars Abrahmsén Giovanni Blandino Andrea Russo Cristina Gamell Stephen B. Fox Catherine Mitchell Elena A. Takano David Byrne Panimaya Jeffreena Miranda Reem Saleh Heather Thorne Shahneen Sandhu Scott G. Williams Simon P. Keam Ygal Haupt Sue Haupt |
| author_facet | Javier Octavio Mejía-Hernández Dinesh Raghu Franco Caramia Nicholas Clemons Kenji Fujihara Thomas Riseborough Amina Teunisse Aart G. Jochemsen Lars Abrahmsén Giovanni Blandino Andrea Russo Cristina Gamell Stephen B. Fox Catherine Mitchell Elena A. Takano David Byrne Panimaya Jeffreena Miranda Reem Saleh Heather Thorne Shahneen Sandhu Scott G. Williams Simon P. Keam Ygal Haupt Sue Haupt |
| author_sort | Javier Octavio Mejía-Hernández |
| collection | DOAJ |
| description | Metastatic prostate cancer is a lethal disease in patients incapable of responding to therapeutic interventions. Invasive prostate cancer spread is caused by failure of the normal anti-cancer defense systems that are controlled by the tumour suppressor protein, p53. Upon mutation, p53 malfunctions. Therapeutic strategies to directly re-empower the growth-restrictive capacities of p53 in cancers have largely been unsuccessful, frequently because of a failure to discriminate responses in diseased and healthy tissues. Our studies sought alternative prostate cancer drivers, intending to uncover new treatment targets. We discovered the oncogenic potency of MDM4 in prostate cancer cells, both in the presence and absence of p53 and also its mutation. We uncovered that sustained depletion of MDM4 is growth inhibitory in prostate cancer cells, involving either apoptosis or senescence, depending on the cell and genetic context. We identified that the potency of MDM4 targeting could be potentiated in prostate cancers with mutant p53 through the addition of a first-in-class small molecule drug that was selected as a p53 reactivator and has the capacity to elevate oxidative stress in cancer cells to drive their death. |
| first_indexed | 2024-03-09T04:38:38Z |
| format | Article |
| id | doaj.art-ff015e55998b4b289710d38ac8d67f09 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-09T04:38:38Z |
| publishDate | 2022-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-ff015e55998b4b289710d38ac8d67f092023-12-03T13:25:06ZengMDPI AGCancers2072-66942022-08-011416394710.3390/cancers14163947Targeting MDM4 as a Novel Therapeutic Approach in Prostate Cancer Independent of p53 StatusJavier Octavio Mejía-Hernández0Dinesh Raghu1Franco Caramia2Nicholas Clemons3Kenji Fujihara4Thomas Riseborough5Amina Teunisse6Aart G. Jochemsen7Lars Abrahmsén8Giovanni Blandino9Andrea Russo10Cristina Gamell11Stephen B. Fox12Catherine Mitchell13Elena A. Takano14David Byrne15Panimaya Jeffreena Miranda16Reem Saleh17Heather Thorne18Shahneen Sandhu19Scott G. Williams20Simon P. Keam21Ygal Haupt22Sue Haupt23Peter MacCallum Cancer Centre, 305 Grattan St, Melbourne, VIC 3000, AustraliaPeter MacCallum Cancer Centre, 305 Grattan St, Melbourne, VIC 3000, AustraliaPeter MacCallum Cancer Centre, 305 Grattan St, Melbourne, VIC 3000, AustraliaPeter MacCallum Cancer Centre, 305 Grattan St, Melbourne, VIC 3000, AustraliaPeter MacCallum Cancer Centre, 305 Grattan St, Melbourne, VIC 3000, AustraliaPeter MacCallum Cancer Centre, 305 Grattan St, Melbourne, VIC 3000, AustraliaDepartment of Cell and Chemical Biology, Leiden University Medical Centre, 2333 Leiden, The NetherlandsDepartment of Cell and Chemical Biology, Leiden University Medical Centre, 2333 Leiden, The NetherlandsAprea Therapeutics AB, 17165 Stockholm, SwedenTranslational Oncology Research Unit, IRCSS Regina Elena National Cancer Institute, 0144 Rome, ItalySurgical Pathology Unit, Department of Research, Advanced Diagnostics and Technological Innovation, IRCSS Regina Elena National Cancer Institute, 0144 Rome, ItalyPeter MacCallum Cancer Centre, 305 Grattan St, Melbourne, VIC 3000, AustraliaPeter MacCallum Cancer Centre, 305 Grattan St, Melbourne, VIC 3000, AustraliaPeter MacCallum Cancer Centre, 305 Grattan St, Melbourne, VIC 3000, AustraliaPeter MacCallum Cancer Centre, 305 Grattan St, Melbourne, VIC 3000, AustraliaPeter MacCallum Cancer Centre, 305 Grattan St, Melbourne, VIC 3000, AustraliaPeter MacCallum Cancer Centre, 305 Grattan St, Melbourne, VIC 3000, AustraliaPeter MacCallum Cancer Centre, 305 Grattan St, Melbourne, VIC 3000, AustraliaPeter MacCallum Cancer Centre, 305 Grattan St, Melbourne, VIC 3000, AustraliaPeter MacCallum Cancer Centre, 305 Grattan St, Melbourne, VIC 3000, AustraliaPeter MacCallum Cancer Centre, 305 Grattan St, Melbourne, VIC 3000, AustraliaPeter MacCallum Cancer Centre, 305 Grattan St, Melbourne, VIC 3000, AustraliaPeter MacCallum Cancer Centre, 305 Grattan St, Melbourne, VIC 3000, AustraliaPeter MacCallum Cancer Centre, 305 Grattan St, Melbourne, VIC 3000, AustraliaMetastatic prostate cancer is a lethal disease in patients incapable of responding to therapeutic interventions. Invasive prostate cancer spread is caused by failure of the normal anti-cancer defense systems that are controlled by the tumour suppressor protein, p53. Upon mutation, p53 malfunctions. Therapeutic strategies to directly re-empower the growth-restrictive capacities of p53 in cancers have largely been unsuccessful, frequently because of a failure to discriminate responses in diseased and healthy tissues. Our studies sought alternative prostate cancer drivers, intending to uncover new treatment targets. We discovered the oncogenic potency of MDM4 in prostate cancer cells, both in the presence and absence of p53 and also its mutation. We uncovered that sustained depletion of MDM4 is growth inhibitory in prostate cancer cells, involving either apoptosis or senescence, depending on the cell and genetic context. We identified that the potency of MDM4 targeting could be potentiated in prostate cancers with mutant p53 through the addition of a first-in-class small molecule drug that was selected as a p53 reactivator and has the capacity to elevate oxidative stress in cancer cells to drive their death.https://www.mdpi.com/2072-6694/14/16/3947MDM4MDMXTP53p53prostate cancereprenetapopt |
| spellingShingle | Javier Octavio Mejía-Hernández Dinesh Raghu Franco Caramia Nicholas Clemons Kenji Fujihara Thomas Riseborough Amina Teunisse Aart G. Jochemsen Lars Abrahmsén Giovanni Blandino Andrea Russo Cristina Gamell Stephen B. Fox Catherine Mitchell Elena A. Takano David Byrne Panimaya Jeffreena Miranda Reem Saleh Heather Thorne Shahneen Sandhu Scott G. Williams Simon P. Keam Ygal Haupt Sue Haupt Targeting MDM4 as a Novel Therapeutic Approach in Prostate Cancer Independent of p53 Status Cancers MDM4 MDMX TP53 p53 prostate cancer eprenetapopt |
| title | Targeting MDM4 as a Novel Therapeutic Approach in Prostate Cancer Independent of p53 Status |
| title_full | Targeting MDM4 as a Novel Therapeutic Approach in Prostate Cancer Independent of p53 Status |
| title_fullStr | Targeting MDM4 as a Novel Therapeutic Approach in Prostate Cancer Independent of p53 Status |
| title_full_unstemmed | Targeting MDM4 as a Novel Therapeutic Approach in Prostate Cancer Independent of p53 Status |
| title_short | Targeting MDM4 as a Novel Therapeutic Approach in Prostate Cancer Independent of p53 Status |
| title_sort | targeting mdm4 as a novel therapeutic approach in prostate cancer independent of p53 status |
| topic | MDM4 MDMX TP53 p53 prostate cancer eprenetapopt |
| url | https://www.mdpi.com/2072-6694/14/16/3947 |
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