Targeting p53 for Melanoma Treatment: Counteracting Tumour Proliferation, Dissemination and Therapeutic Resistance
| Autor: | Joana B. Loureiro, Liliana Raimundo, Marco G. Alves, Célia Gomes, Maria Inês Almeida, Carla Carvalho, Lucília Saraiva, José Luis Costa, Nuno R. Lima, Valentina Barcherini, Juliana Calheiros, Maria M. M. Santos |
|---|---|
| Přispěvatelé: | Universidade do Minho |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
p53 Tryptophanol-derived oxazoloisoindolinone Cancer Research Angiogenesis medicine.medical_treatment Dacarbazine lcsh:RC254-282 Article Metastasis Targeted therapy 03 medical and health sciences 0302 clinical medicine medicine melanoma metastasis Vemurafenib Melanoma drug resistance Cell growth business.industry medicine.disease targeted therapy lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens 3. Good health 030104 developmental biology Oncology Drug resistance 030220 oncology & carcinogenesis Cancer research Skin cancer tryptophanol-derived oxazoloisoindolinone business medicine.drug |
| Zdroj: | Cancers, Vol 13, Iss 1648, p 1648 (2021) Cancers Volume 13 Issue 7 Repositório Científico de Acesso Aberto de Portugal Repositório Científico de Acesso Aberto de Portugal (RCAAP) instacron:RCAAP |
| ISSN: | 2072-6694 |
| Popis: | 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. 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). |
| Databáze: | OpenAIRE |
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