RESUMO
Compared with previous standards of care (including chemotherapy, radiotherapy, and surgery), cancer immunotherapy has brought significant improvements for patients in terms of survival and quality of life. Immunotherapy has now firmly established itself as a novel pillar of cancer care, from the metastatic stage to the adjuvant and neoadjuvant settings in numerous cancer types. In this review article, we highlight how the history of cancer immunotherapy paved the way for discoveries that are now part of the standard of care. We also highlight the current pitfalls and limitations of cancer checkpoint immunotherapy and how novel research in the fields of personalized cancer vaccines, autoimmunity, the microbiome, the tumour microenvironment, and metabolomics is aiming to solve those challenges.
Assuntos
Imunoterapia/métodos , Neoplasias/tratamento farmacológico , HumanosRESUMO
Cdc kinase subunit (Cks) proteins Cks1 and Cks2 are adaptor-like proteins that bind many cyclin-dependent kinases. A wealth of clinical data has shown that Cks proteins are overexpressed in many types of human cancers and this often correlates with increased tumor aggressiveness. Previously, we showed that Cks overexpression abrogates the intra-S-phase checkpoint, a major barrier to oncogene-mediated transformation. Interestingly, the intra-S-phase checkpoint is crucial for the cellular response to replication stress, a major pathway of apoptosis induction by many chemotherapeutic agents. Here, we demonstrate cancer cells that overexpress Cks1 or Cks2 override the intra-S-phase checkpoint in the presence of replication stress-inducing chemotherapies such as 5-Fluorouracil (5-FU) and methotrexate (MTX) leading to enhanced sensitivity in vitro and in vivo. Furthermore, enforced expression of Cks1 in an MTX-resistant breast cancer cell line was found to restore drug sensitivity. Our results suggest that Cks proteins are important determinants of apoptosis induction of replication stress-inducing chemotherapies such as 5-FU.
Assuntos
Antimetabólitos Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/enzimologia , Quinases Ciclina-Dependentes/biossíntese , Dano ao DNA , Fluoruracila/farmacologia , Animais , Apoptose/efeitos dos fármacos , Neoplasias da Mama/genética , Linhagem Celular Tumoral , Quinases Ciclina-Dependentes/metabolismo , Replicação do DNA/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Humanos , Células MCF-7 , Camundongos , Camundongos Nus , Pontos de Checagem da Fase S do Ciclo Celular/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The progression of cancers from primary tumors to invasive and metastatic stages accounts for the overwhelming majority of cancer deaths. Understanding the molecular events which promote metastasis is thus critical in the clinic. Translational control is emerging as an important factor in tumorigenesis. The messenger RNA (mRNA) cap-binding protein eIF4E is an oncoprotein that has an important role in cancer initiation and progression. eIF4E must be phosphorylated to promote tumor development. However, the role of eIF4E phosphorylation in metastasis is not known. Here, we show that mice in which eukaryotic translation initiation factor 4E (eIF4E) cannot be phosphorylated are resistant to lung metastases in a mammary tumor model, and that cells isolated from these mice exhibit impaired invasion. We also demonstrate that transforming growth factor-beta (TGFß) induces eIF4E phosphorylation to promote the translation of Snail and Mmp-3 mRNAs, and the induction of epithelial-to-mesenchymal transition (EMT). Furthermore, we describe a new model wherein EMT induced by TGFß requires translational activation via the non-canonical TGFß signaling branch acting through eIF4E phosphorylation.
Assuntos
Transição Epitelial-Mesenquimal , Fator de Iniciação 4E em Eucariotos/metabolismo , Neoplasias Pulmonares/secundário , Neoplasias Mamárias Experimentais/patologia , Metaloproteinase 3 da Matriz/metabolismo , Fatores de Transcrição/biossíntese , Fator de Crescimento Transformador beta/metabolismo , Animais , Linhagem Celular Tumoral , Movimento Celular , Transformação Celular Neoplásica/genética , Fator de Iniciação 4E em Eucariotos/genética , Feminino , Neoplasias Pulmonares/genética , Neoplasias Mamárias Experimentais/metabolismo , Metaloproteinase 3 da Matriz/genética , Camundongos , Fosforilação , Biossíntese de Proteínas/genética , RNA Mensageiro/metabolismo , Fatores de Transcrição da Família Snail , Fatores de Transcrição/genéticaRESUMO
Darinaparsin (Dar) is a more potent cytotoxic arsenical than arsenic trioxide (ATO). We hypothesized that the increased cytotoxicity of Dar may be because of a decreased cytoprotective response. We observed that, unlike ATO, Dar does not induce heme oxygenase-1 (HO-1), even though it induces expression of other nuclear factor (erythroid-derived 2)-like 2 (NRF2)-dependent detoxifying enzymes to a greater extent than ATO, in both cancer cell lines and patient-derived leukemic cells. This strengthens the emerging evidence, showing that response to reactive oxygen species (ROS) is stimuli specific. Dar treatment prevents recruitment of the transcriptional coregulator Brahma-related gene 1 (BRG1) to the HMOX1 promoter, which is required for HMOX1 expression. The inability of Dar to induce HO-1 correlates with arrest in G2/M cell cycle phase and BRG1 phosphorylation. Inhibition of HO-1 increases the toxicity of ATO, but has no effect on Dar-induced apoptosis. Accordingly, the lack of HO-1 induction is involved in Dar's enhanced antileukemic properties. Our data highlight cytoprotective responses mediated by HO-1 and BRG1 as a novel target for enhancing the therapeutic range of arsenicals.
Assuntos
Arsenicais/farmacologia , Crise Blástica/patologia , Citoproteção/efeitos dos fármacos , DNA Helicases/metabolismo , Glutationa/análogos & derivados , Heme Oxigenase-1/metabolismo , Leucemia Promielocítica Aguda/patologia , Proteínas Nucleares/metabolismo , Fatores de Transcrição/metabolismo , Apoptose/efeitos dos fármacos , Trióxido de Arsênio , Crise Blástica/tratamento farmacológico , Crise Blástica/metabolismo , Western Blotting , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Imunoprecipitação da Cromatina , DNA Helicases/genética , Citometria de Fluxo , Glutationa/farmacologia , Heme Oxigenase-1/genética , Humanos , Leucemia Promielocítica Aguda/tratamento farmacológico , Leucemia Promielocítica Aguda/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Proteínas Nucleares/genética , Óxidos/farmacologia , Fosforilação/efeitos dos fármacos , Regiões Promotoras Genéticas/genética , RNA Mensageiro/genética , Espécies Reativas de Oxigênio/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Transcrição/genética , Células Tumorais CultivadasRESUMO
Stats (signal transducers and activators of transcription) are latent cytoplasmic transcription factors that on a specific stimulus migrate to the nucleus and exert their transcriptional activity. Here we report a novel signaling pathway whereby RhoA can efficiently modulate Stat3 transcriptional activity by inducing its simultaneous tyrosine and serine phosphorylation. Tyrosine phosphorylation is exerted via a member of the Src family of kinases (SrcFK) and JAK2, whereas the JNK pathway mediates serine phosphorylation. Furthermore, cooperation of both tyrosine as well as serine phosphorylation is necessary for full activation of Stat3. Induction of Stat3 activity depends on the effector domain of RhoA and correlates with induction of both Src Kinase-related and JNK activities. Activation of Stat3 has biological implications. Coexpression of an oncogenic version of RhoA along with the wild-type, nontransforming Stat3 gene, significantly enhances its oncogenic activity on human HEK cells, suggesting that Stat3 is an essential component of RhoA-mediated transformation. In keeping with this, dominant negative Stat3 mutants or inhibition of its tyrosine or serine phosphorylation completely abrogate RhoA oncogenic potential. Taken together, these results indicate that Stat3 is an important player in RhoA-mediated oncogenic transformation, which requires simultaneous phosphorylation at both tyrosine and serine residues by specific signaling events triggered by RhoA effectors.