Targeting p53 for melanoma treatment: counteracting tumour proliferation, dissemination and therapeutic resistance
Autor(a) principal: | |
---|---|
Data de Publicação: | 2021 |
Outros Autores: | , , , , , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
Texto Completo: | http://hdl.handle.net/1822/73358 |
Resumo: | Melanoma is the deadliest form of skin cancer, primarily due to its high metastatic propensity and therapeutic resistance in advanced stages. The frequent inactivation of the p53 tumour suppressor protein in melanomagenesis may predict promising outcomes for p53 activators in melanoma therapy. Herein, we aimed to investigate the antitumor potential of the p53-activating agent SLMP53-2 against melanoma. Two- and three-dimensional cell cultures and xenograft mouse models were used to unveil the antitumor activity and the underlying molecular mechanism of SLMP53-2 in melanoma. SLMP53-2 inhibited the growth of human melanoma cells in a p53-dependent manner through induction of cell cycle arrest and apoptosis. Notably, SLMP53-2 induced p53 stabilization by disrupting the p53–MDM2 interaction, enhancing p53 transcriptional activity. It also promoted the expression of p53-regulated microRNAs (miRNAs), including miR-145 and miR-23a. Moreover, it displayed anti-invasive and antimigratory properties in melanoma cells by inhibiting the epithelial-to-mesenchymal transition (EMT), angiogenesis and extracellular lactate production. Importantly, SLMP53-2 did not induce resistance in melanoma cells. Additionally, it synergized with vemurafenib, dacarbazine and cisplatin, and resensitized vemurafenib-resistant cells. SLMP53-2 also exhibited antitumor activity in human melanoma xenograft mouse models by repressing cell proliferation and EMT while stimulating apoptosis. This work discloses the p53-activating agent SLMP53-2 which has promising therapeutic potential in advanced melanoma, either as a single agent or in combination therapy. By targeting p53, SLMP53-2 may counteract major features of melanoma aggressiveness. |
id |
RCAP_563e5c2257055b0593fb80b0e5b1ca1c |
---|---|
oai_identifier_str |
oai:repositorium.sdum.uminho.pt:1822/73358 |
network_acronym_str |
RCAP |
network_name_str |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
repository_id_str |
7160 |
spelling |
Targeting p53 for melanoma treatment: counteracting tumour proliferation, dissemination and therapeutic resistanceMelanomaMetastasisDrug resistanceTargeted therapyp53Tryptophanol-derived oxazoloisoindolinoneMelanoma is the deadliest form of skin cancer, primarily due to its high metastatic propensity and therapeutic resistance in advanced stages. The frequent inactivation of the p53 tumour suppressor protein in melanomagenesis may predict promising outcomes for p53 activators in melanoma therapy. Herein, we aimed to investigate the antitumor potential of the p53-activating agent SLMP53-2 against melanoma. Two- and three-dimensional cell cultures and xenograft mouse models were used to unveil the antitumor activity and the underlying molecular mechanism of SLMP53-2 in melanoma. SLMP53-2 inhibited the growth of human melanoma cells in a p53-dependent manner through induction of cell cycle arrest and apoptosis. Notably, SLMP53-2 induced p53 stabilization by disrupting the p53–MDM2 interaction, enhancing p53 transcriptional activity. It also promoted the expression of p53-regulated microRNAs (miRNAs), including miR-145 and miR-23a. Moreover, it displayed anti-invasive and antimigratory properties in melanoma cells by inhibiting the epithelial-to-mesenchymal transition (EMT), angiogenesis and extracellular lactate production. Importantly, SLMP53-2 did not induce resistance in melanoma cells. Additionally, it synergized with vemurafenib, dacarbazine and cisplatin, and resensitized vemurafenib-resistant cells. SLMP53-2 also exhibited antitumor activity in human melanoma xenograft mouse models by repressing cell proliferation and EMT while stimulating apoptosis. This work discloses the p53-activating agent SLMP53-2 which has promising therapeutic potential in advanced melanoma, either as a single agent or in combination therapy. By targeting p53, SLMP53-2 may counteract major features of melanoma aggressiveness.This work received financial support from PT national funds (FCT/MCTES, Fundação para a Ciência e Tecnologia and Ministério da Ciência, Tecnologia e Ensino Superior) through LAQV/REQUIMTE (UID/QUI/50006/2020), iMed.ULisboa (UIDB/04138/2020), and PTDC/QUIQOR/29664/2017, PTDC/MEC-ONC/32018/2017. We thank FCT for the fellowships SFRH/BD/ 128673/2017 (J. Loureiro), 2020.04613.BD (J. Calheiros), PD/BD/143126/2019 (V. Barcherini).Multidisciplinary Digital Publishing Institute (MDPI)Universidade do MinhoLoureiro, Joana B.Raimundo, LilianaCalheiros, JulianaCarvalho, CarlaBarcherini, ValentinaLima, Nuno R.Gomes, CéliaAlmeida, Maria InêsAlves, Marco G.Costa, José LuísSantos, Maria M. M.Saraiva, Lucília2021-04-012021-04-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/1822/73358engLoureiro, J.B.; Raimundo, L.; Calheiros, J.; Carvalho, C.; Barcherini, V.; Lima, N.R.; Gomes, C.; Almeida, M.I.; Alves, M.G.; Costa, J.L.; Santos, M.M.M.; Saraiva, L. Targeting p53 for Melanoma Treatment: Counteracting Tumour Proliferation, Dissemination and Therapeutic Resistance. Cancers 2021, 13, 1648. https://doi.org/10.3390/cancers130716482072-669410.3390/cancers13071648https://www.mdpi.com/2072-6694/13/7/1648info:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2023-07-21T12:21:13Zoai:repositorium.sdum.uminho.pt:1822/73358Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T19:14:26.183861Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse |
dc.title.none.fl_str_mv |
Targeting p53 for melanoma treatment: counteracting tumour proliferation, dissemination and therapeutic resistance |
title |
Targeting p53 for melanoma treatment: counteracting tumour proliferation, dissemination and therapeutic resistance |
spellingShingle |
Targeting p53 for melanoma treatment: counteracting tumour proliferation, dissemination and therapeutic resistance Loureiro, Joana B. Melanoma Metastasis Drug resistance Targeted therapy p53 Tryptophanol-derived oxazoloisoindolinone |
title_short |
Targeting p53 for melanoma treatment: counteracting tumour proliferation, dissemination and therapeutic resistance |
title_full |
Targeting p53 for melanoma treatment: counteracting tumour proliferation, dissemination and therapeutic resistance |
title_fullStr |
Targeting p53 for melanoma treatment: counteracting tumour proliferation, dissemination and therapeutic resistance |
title_full_unstemmed |
Targeting p53 for melanoma treatment: counteracting tumour proliferation, dissemination and therapeutic resistance |
title_sort |
Targeting p53 for melanoma treatment: counteracting tumour proliferation, dissemination and therapeutic resistance |
author |
Loureiro, Joana B. |
author_facet |
Loureiro, Joana B. Raimundo, Liliana Calheiros, Juliana Carvalho, Carla Barcherini, Valentina Lima, Nuno R. Gomes, Célia Almeida, Maria Inês Alves, Marco G. Costa, José Luís Santos, Maria M. M. Saraiva, Lucília |
author_role |
author |
author2 |
Raimundo, Liliana Calheiros, Juliana Carvalho, Carla Barcherini, Valentina Lima, Nuno R. Gomes, Célia Almeida, Maria Inês Alves, Marco G. Costa, José Luís Santos, Maria M. M. Saraiva, Lucília |
author2_role |
author author author author author author author author author author author |
dc.contributor.none.fl_str_mv |
Universidade do Minho |
dc.contributor.author.fl_str_mv |
Loureiro, Joana B. Raimundo, Liliana Calheiros, Juliana Carvalho, Carla Barcherini, Valentina Lima, Nuno R. Gomes, Célia Almeida, Maria Inês Alves, Marco G. Costa, José Luís Santos, Maria M. M. Saraiva, Lucília |
dc.subject.por.fl_str_mv |
Melanoma Metastasis Drug resistance Targeted therapy p53 Tryptophanol-derived oxazoloisoindolinone |
topic |
Melanoma Metastasis Drug resistance Targeted therapy p53 Tryptophanol-derived oxazoloisoindolinone |
description |
Melanoma is the deadliest form of skin cancer, primarily due to its high metastatic propensity and therapeutic resistance in advanced stages. The frequent inactivation of the p53 tumour suppressor protein in melanomagenesis may predict promising outcomes for p53 activators in melanoma therapy. Herein, we aimed to investigate the antitumor potential of the p53-activating agent SLMP53-2 against melanoma. Two- and three-dimensional cell cultures and xenograft mouse models were used to unveil the antitumor activity and the underlying molecular mechanism of SLMP53-2 in melanoma. SLMP53-2 inhibited the growth of human melanoma cells in a p53-dependent manner through induction of cell cycle arrest and apoptosis. Notably, SLMP53-2 induced p53 stabilization by disrupting the p53–MDM2 interaction, enhancing p53 transcriptional activity. It also promoted the expression of p53-regulated microRNAs (miRNAs), including miR-145 and miR-23a. Moreover, it displayed anti-invasive and antimigratory properties in melanoma cells by inhibiting the epithelial-to-mesenchymal transition (EMT), angiogenesis and extracellular lactate production. Importantly, SLMP53-2 did not induce resistance in melanoma cells. Additionally, it synergized with vemurafenib, dacarbazine and cisplatin, and resensitized vemurafenib-resistant cells. SLMP53-2 also exhibited antitumor activity in human melanoma xenograft mouse models by repressing cell proliferation and EMT while stimulating apoptosis. This work discloses the p53-activating agent SLMP53-2 which has promising therapeutic potential in advanced melanoma, either as a single agent or in combination therapy. By targeting p53, SLMP53-2 may counteract major features of melanoma aggressiveness. |
publishDate |
2021 |
dc.date.none.fl_str_mv |
2021-04-01 2021-04-01T00:00:00Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://hdl.handle.net/1822/73358 |
url |
http://hdl.handle.net/1822/73358 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
Loureiro, J.B.; Raimundo, L.; Calheiros, J.; Carvalho, C.; Barcherini, V.; Lima, N.R.; Gomes, C.; Almeida, M.I.; Alves, M.G.; Costa, J.L.; Santos, M.M.M.; Saraiva, L. Targeting p53 for Melanoma Treatment: Counteracting Tumour Proliferation, Dissemination and Therapeutic Resistance. Cancers 2021, 13, 1648. https://doi.org/10.3390/cancers13071648 2072-6694 10.3390/cancers13071648 https://www.mdpi.com/2072-6694/13/7/1648 |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
application/pdf |
dc.publisher.none.fl_str_mv |
Multidisciplinary Digital Publishing Institute (MDPI) |
publisher.none.fl_str_mv |
Multidisciplinary Digital Publishing Institute (MDPI) |
dc.source.none.fl_str_mv |
reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação instacron:RCAAP |
instname_str |
Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
instacron_str |
RCAAP |
institution |
RCAAP |
reponame_str |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
collection |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
repository.name.fl_str_mv |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
repository.mail.fl_str_mv |
|
_version_ |
1799132586776199168 |