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[This corrects the article DOI: 10.18632/oncotarget.20469.].
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The actual strategy to improve current therapies in advanced prostate cancer involves targeting genes activated by androgen withdrawal, either to delay or prevent the emergence of the castration-refractory phenotype. However, these genes are often implicated in several physiological processes, and long-term inhibition of survival proteins might be accompanied with cytotoxic effects. To avoid this problem, an alternative therapeutic strategy relies on the identification and use of compounds that disrupt specific protein-protein interactions involved in androgen withdrawal. Specifically, the interaction of the chaperone protein Hsp27 with the initiation factor eIF4E leads to the protection of protein synthesis initiation process and enhances cell survival during cell stress induced by castration or chemotherapy. Thus, in this work we aimed at i) identifying the interaction site of the Hsp27/eIF4E complex and ii) interfere with the relevant protein/protein association mechanism involved in castration-resistant progression of prostate cancer. By a combination of experimental and modeling techniques, we proved that eIF4E interacts with the C-terminal part of Hsp27, preferentially when Hsp27 is phosphorylated. We also observed that the loss of this interaction increased cell chemo-and hormone-sensitivity. In order to find a potential inhibitor of Hsp27/eIF4E interaction, BRET assays in combination with molecular simulations identified the phenazine derivative 14 as the compound able to efficiently interfere with this protein/protein interaction, thereby inhibiting cell viability and increasing cell death in chemo- and castration-resistant prostate cancer models in vitro and in vivo.
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Prostate cancer (PC) is the second most common cause of cancer-related mortality in men in the western world after lung cancer. Many patients are not candidates for resection given the advanced stage of their cancer. The primary treatment for advanced PC is the castration therapy which supresses the production of androgens, hormone that promotes PC growth. Despite the efficiency of the castration therapy, most patients develop castration resistant disease which remains uncurable. Clearly, novel approaches are required to effectively treat castration resistant PC (CRPC). New strategies that identify the molecular mechanisms by which PC becomes resistant to conventional therapies may enable the identification of novel therapeutic targets that could improve clinical outcome. Recent studies have demonstrated the implication of TCTP's over-expression in PC and CRPC, and its role in resistance to treatment. TCTP's interaction with p53 and their negative feedback loop regulation have also been described to be causal for PC progression and invasion. A novel nanotherapy that inhibits TCTP has been developed as a new therapeutical strategy in CRPC. This chapter will highlight the role of TCTP as new therapeutic target in PC, in particular, therapy-resistant advanced PC and report the development of novel nanotherapy against TCTP that restore treatment-sensitivity in CRPC that deserve to be tested in clinical trial.
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Biomarcadores Tumorais/antagonistas & inibidores , Biomarcadores Tumorais/metabolismo , Neoplasias de Próstata Resistentes à Castração/patologia , Neoplasias de Próstata Resistentes à Castração/terapia , Androgênios/metabolismo , Castração , Progressão da Doença , Humanos , Masculino , Invasividade Neoplásica , Neoplasias de Próstata Resistentes à Castração/metabolismo , Proteína Tumoral 1 Controlada por TraduçãoRESUMO
Translationally controlled tumor protein (TCTP) has been implicated in a plethora of important cellular processes related to cell growth, cell cycle progression, malignant transformation and inhibition of apoptosis. Therefore, TCTP is now recognized as a potential therapeutic target in several cancers including prostate, breast and lung cancers. We previously showed that TCTP is overexpressed in castration-resistant prostate cancer (CRPC), and it has been implicated resistance to treatment. Recently, we developed TCTP antisense oligonucleotides (ASOs) to inhibit TCTP expression. However, the intracellular delivery and silencing activity of these oligonucleotides remains a challenge, and depend on the use of transfection agents and delivery systems. Here we show that lipid-modified ASO (LASOs) has improved penetration and efficiency in inhibiting TCTP expression in the absence of additional transfection agents, both in vitro and in vivo. Transfection with TCTP-LASO led to rapid and prolonged internalization via macropinocytosis, TCTP downregulation and significant decreased cell viability. We also show that lipid-modification led to delayed tumor progression in CRPC xenografts models, with no significant toxic effects observed.
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Biomarcadores Tumorais/genética , Oligonucleotídeos Antissenso/administração & dosagem , Oligonucleotídeos Antissenso/genética , Neoplasias de Próstata Resistentes à Castração/terapia , Transfecção/métodos , Animais , Linhagem Celular Tumoral , Sobrevivência Celular , Regulação para Baixo , Regulação Neoplásica da Expressão Gênica , Terapia Genética/métodos , Humanos , Lipídeos/química , Masculino , Camundongos , Camundongos Nus , Oligonucleotídeos Antissenso/química , Oligonucleotídeos Antissenso/uso terapêutico , Pinocitose , Neoplasias de Próstata Resistentes à Castração/genética , Proteína Tumoral 1 Controlada por TraduçãoRESUMO
Cancer cells depend on cap-dependent translation more than normal tissue. This explains the emergence of proteins involved in the cap-dependent translation as targets for potential anticancer drugs. Cap-dependent translation starts when eIF4E binds to mRNA cap domain. This review will present eIF4E's structure and functions. It will also expose the use of eIF4E as a therapeutic target in cancer.
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Fator de Iniciação 4E em Eucariotos/química , Fator de Iniciação 4E em Eucariotos/genética , Terapia de Alvo Molecular , Neoplasias/genética , Fator de Iniciação 4E em Eucariotos/biossíntese , Humanos , Neoplasias/terapia , Conformação Proteica , RNA Mensageiro/biossíntese , Relação Estrutura-Atividade , Transcrição GênicaRESUMO
Prostate cancer has become a real public health issue in industrialized countries, mainly due to patients' relapse by castration-refractory disease after androgen ablation. Castration-resistant prostate cancer is an incurable and highly aggressive terminal stage of prostate cancer, seriously jeopardizing the patient's quality of life and lifespan. The management of castration-resistant prostate cancer is complex and has opened new fields of research during the last decade leading to an improved understanding of the biology of the disease and the development of new therapies. Most advanced tumors resistant to therapy still maintain the androgen receptor-pathway, which plays a central role for survival and growth of most castration-resistant prostate cancers. Many mechanisms induce the emergence of the castration resistant phenotype through this pathway. However some non-related AR pathways like neuroendocrine cells or overexpression of anti-apoptotic proteins like Hsp27 are described to be involved in CRPC progression. More recently, loss of expression of tumor suppressor gene, post-transcriptional modification using miRNA, epigenetic alterations, alternatif splicing and gene fusion became also hallmarks of castration-resistant prostate cancer. This review presents an up-to-date overview of the androgen receptor-related mechanisms as well as the latest evidence of the non-AR-related mechanisms underlying castration-resistant prostate cancer progression.
