RESUMO
Cycloartenyl ferulate (CF) is abundant in brown rice with multiple biologic functions. It has been reported to possess antitumor activity; however, the related mechanism of action of CF has not been clarified. Herein, we unexpectedly uncover the immunological regulation effects of CF and its molecular mechanism. We discovered that CF directly enhanced the killing capacity of natural killer (NK) cells for various cancer cells in vitro. In vivo, CF also improved cancer surveillance in mouse models of lymphoma clearance and metastatic melanoma dependent on NK cells. In addition, CF promoted anticancer efficacy of the anti-PD1 antibody with improvement of tumor immune microenvironment. Mechanistically, we first unveiled that CF acted on the canonical JAK1/2-STAT1 signaling pathway to enhance the immunity of the NK cells by selectively binding to interferon γ receptor 1. Collectively, our results indicate that CF is a promising immunoregulation agent worthy of attention in clinical application in the future. Due to broad biological significance of interferon γ, our findings also provide a capability to understand the diverse functions of CF.
Assuntos
Ácidos Cumáricos , Células Matadoras Naturais , Neoplasias , Receptores de Interferon , Animais , Camundongos , Interferon gama/imunologia , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Neoplasias/imunologia , Microambiente Tumoral , Ácidos Cumáricos/farmacologia , Receptores de Interferon/imunologia , Receptor de Interferon gamaRESUMO
Metastasis accounts for the vast majority of deaths in breast cancer, and novel and effective treatments to inhibit cancer metastasis remain urgently developed. The expression level of heat shock protein 90 (HSP90) in invasive breast cancer tissue is higher than in adjacent non-cancerous tissue. In the present study, we investigated the inhibitory effect of penisuloxazin A (PNSA), a novel C- terminal inhibitor of HSP90, on metastasis of breast cancer cells and related mechanism in vitro. We found that PNSA obviously affected adhesion, migration, and invasion of triple-negative breast cancer (TNBC) MDA-MB-231 cells and Trastuzumab-resistant JIMT-1 cells. Furthermore, PNSA was capable of reversing epithelial-mesenchymal transformation (EMT) of MDA-MB-231 cells with change of cell morphology. PNSA increases E-cadherin expression followed by decreasing amounts of N-cadherin, vimentin, and matrix metalloproteinases9 (MMP9) and proteolytic activity of matrix metalloproteinases2 (MMP2) and MMP9. Comparatively, the N-terminal inhibitor of HSP90 17-allyl-17-demethoxygeldanamycin (17-AAG) had no effect on EMT of MDA-MB-231 cells. PNSA was uncovered to reduce the stability of epidermal growth factor receptor (EGFR) and fibroblast growth factor receptor (FGFR) proteins and thereby inhibiting their downstream signaling transductions by inhibition of HSP90. In addition, PNSA reduced the expression of programmed cell death-ligand 1 (PD-L1) to promote natural killer (NK) cells to kill breast cancer cells with a dose far less than that of cytotoxicity to NK cell itself, implying the potential of PNSA to enhance immune surveillance against metastasis in vivo. All these results indicate that PNSA is a promising anti-metastasis agent worthy of being studied in the future.
Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Antineoplásicos/administração & dosagem , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Resistencia a Medicamentos Antineoplásicos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Feminino , Humanos , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/metabolismo , Metástase Neoplásica/prevenção & controle , Trastuzumab/farmacologia , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologiaRESUMO
Phosphoglycerate kinase 1(PGK1) is an important enzyme in the metabolic glycolysis pathway. Nowadays, PGK1 is an appealing therapeutic target for multiple cancers. However, no effective inhibitor of PGK1 has been reported. In this study, we demonstrate that Ilicicolin H a 5-(4-hydroxyphenyl)-pyridone with a decalin ring system and a non-ATP-competitive inhibitor of PGK1, inhibits the proliferation and promotes apoptosis of Hepatocellular carcinoma (HCC). Many cancer cells display enhanced glycolysis which is critical for tumor development. Here we identified that Ilicicolin H can target PGK1 in vitro to inhibit the lactate production and glucose uptake of HCC cells. These findings suggest that the PGK1 inhibitor- Ilicicolin H is a promising anticancer agent and may provide a better therapeutic strategy for HCC treatment in the future.
Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/metabolismo , Fosfoglicerato Quinase/genética , Fosfoglicerato Quinase/metabolismo , Linhagem Celular Tumoral , Glicólise , Proliferação de CélulasRESUMO
Penisuloxazin A (PNSA), a new compound from the fungus, is a novel C-terminal Hsp90 inhibitor reported by us before. It has been reported to possess antitumor activity and suppresses metastasis of breast cancer cells. However, the influence of PNSA on T cells is not fully understood. Here, we found that PNSA was much less toxic to lymphocytes than to tumor cells and it had no significant effect on populations of CD3+, CD4+ and CD8+ T lymphocytes. We discovered that PNSA directly enhanced the killing capacities of the CD8+ T and CD3+CD25- to CT26 cells, but not that of CD3+ cells due to the increase of Treg cells. What's more, PNSA pretreated tumor cells increase the sensitivity to CD8+ T cells mainly through the degradation of client protein of Hsp90 and declination of PD-L1 expression. Eventually, PNSA enhanced the killing ability of CD8+ and CD3+ T cells by simultaneously acting on lymphocytes and cancer cells. In vivo experiments, PNSA exhibited inhibition effects in the colon adenocarcinoma with increase of CD8 T cell infiltration in tumor tissues. All these results indicate that the novel Hsp90 C-terminal inhibitor-PNSA can promote lytic T cell immunological function to improve anticancer effect of PNSA, which provides a better foundation for anticancer drug development of PNSA in future.
Assuntos
Adenocarcinoma , Neoplasias do Colo , Humanos , Linfócitos T CD8-Positivos , Adenocarcinoma/metabolismo , Neoplasias do Colo/metabolismo , Linfócitos T Reguladores/metabolismo , Proteínas de Choque Térmico/metabolismoRESUMO
PD-L1 is abnormally regulated in many cancers and is critical for immune escape. Fully understanding the regulation of PD-L1 expression is vital for improving the clinical efficacy of relevant anticancer agents. TGF-ß plays an important role in the low reactivity of PD-1/PD-L1 antibody immunotherapy. However, it is not very clear whether and how TGF-ß affects PD-L1 expression. In the present study, we show that TGF-ß upregulates the expression of the transcriptional coactivator MRTF-A in non-small-cell lung cancer cells, which subsequently interacts with NF-κB/p65 rather than SRF to facilitate the binding of NF-κB/p65 to the PDL1 promoter, thereby activating the transcription and expression of PD-L1. This leads to the immune escape of NSCLC cells. This process is dependent on the activation of the TGF-ß signaling pathway. In vivo, inhibition of MRTF-A effectively suppresses the growth of lung tumor syngrafts with enrichment of NK and T cells in tumor tissue. Our study defines a new signaling pathway that regulates the transcription and expression of PD-L1 upon TGF-ß treatment, which may have a significant impact on research into the application of immunotherapy in treating lung cancer.
Assuntos
Antígeno B7-H1/genética , Carcinoma Pulmonar de Células não Pequenas/etiologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Evasão da Resposta Imune/genética , Neoplasias Pulmonares/etiologia , Neoplasias Pulmonares/metabolismo , Transativadores/metabolismo , Fator de Transcrição RelA/metabolismo , Animais , Biomarcadores , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Modelos Animais de Doenças , Suscetibilidade a Doenças , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Xenoenxertos , Humanos , Neoplasias Pulmonares/patologia , Camundongos , Modelos Biológicos , Complexo de Endopeptidases do Proteassoma/metabolismo , Transdução de Sinais , Fator de Crescimento Transformador beta/metabolismo , Ubiquitina/metabolismoRESUMO
Phosphoglycerate kinase 1 (PGK1) acts as both a glycolytic enzyme and a protein kinase playing critical roles in cancer progression, thereby being regarded as an attractive therapeutic target for cancer treatment. However, no effective inhibitor of PGK1 has been reported. Here, we demonstrate that GQQ-792, a thiodiketopiperazine derivative from marine nature products, is a non-ATP-competitive inhibitor of PGK1 with the disulfide group within the structure of GQQ-792 as a key pharmacophore. The disulfide group of GQQ-792 binds to Cys379 and Cys380 of PGK1, resulting in occlusion of ATP from binding to PGK1. GQQ-792 treatment blocks hypoxic condition- and EGF stimulation-enhanced protein kinase activity of PGK1 that phosphorylates PDHK1 at T338 in glioblastoma cells; this treatment leads to decreased lactate production and glucose uptake, and subsequent apoptosis of glioblastoma cells. Animal studies reveal that GQQ-792 significantly inhibits the growth of tumor derived from glioblastoma cells. These findings underscore the potential of GQQ-792 as a promising anticancer agent and pave an avenue to further optimize the structure of GQQ-792 basing on its target molecule and pharmacophore in future.