RESUMO
Hypoxia, a common feature of solid tumors, can promote chemoresistance in cancer cells. PRMT5 mediates various cellular processes involved in cancer development and progression. However, the role of PRMT5 in hypoxia-induced chemoresistance is unclear. In this study, hypoxia upregulated PRMT5 expression in lung cancer cells. Additionally, PRMT5 overexpression promoted cancer cell resistance to carboplatin. In carboplatin-resistant cancer cells, PRMT5 overexpression promoted the methylation of ULK1, a critical regulator of autophagy. ULK1 hypermethylation leads to the upregulation of autophagy, which can improve the survival of cancer cells under hypoxic conditions. Furthermore, this study demonstrated that the PRMT5 inhibitor C9 significantly enhanced the sensitivity of lung cancer cells to carboplatin. These findings suggest that targeting PRMT5-mediated autophagy with C9 can overcome hypoxia-induced carboplatin resistance and improve the efficacy of chemotherapy in patients with cancer.
Assuntos
Neoplasias Pulmonares , Humanos , Carboplatina/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Pulmão/metabolismo , Hipóxia , Autofagia , Linhagem Celular Tumoral , Proteína-Arginina N-Metiltransferases/genética , Proteína-Arginina N-Metiltransferases/metabolismoRESUMO
1,7-Bis(4-hydroxyphenyl)-1,4-heptadien-3-one (EB30) is a diarylheptanoid-like compound isolated from Viscum coloratum. This curcumin analog exhibits significant cytotoxic activity against HeLa, SGC-7901, and MCF-7 cells. However, little is known about the anticancer effects and mechanisms of EB30 in human lung cancer. The current study reports that EB30 significantly reduced the cell viability of A549 and NCI-H292 human lung cancer cells. Further examination revealed that EB30 not only induced cell cycle arrest and promoted the generation of reactive oxygen species (ROS) but also induced cell apoptosis through the intrinsic and extrinsic signaling pathways. Furthermore, EB30 upregulated the expression levels of p-ERK1/2 and p-P90RSK, whereas downregulating the phosphorylation of Akt and P70RSK. Cell viability was further inhibited by the combination of EB30 with LY294002 (a specific PI3K inhibitor) or U0126 (a MEK inhibitor). The current study indicates that EB30 is a potential anticancer agent that induces cell apoptosis via suppression of the PI3K/Akt pathway and activation of the ERK1/2 pathway.
Assuntos
Antineoplásicos/farmacologia , Curcumina/análogos & derivados , Neoplasias Pulmonares , Extratos Vegetais/farmacologia , Transdução de Sinais/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/fisiologia , Fosfatidilinositol 3-Quinases/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Viscum/químicaRESUMO
Cervical cancer (CC) is the most common gynecologic malignancy, which seriously threatens the health of women. Lipid metabolism is necessary for tumor proliferation and metastasis. However, the molecular mechanism of the relationship between CC and lipid metabolism remains poorly defined. We revealed the expression of IGF2BP3 in CC exceeded adjacent tissues, and was positively associated with tumor stage using human CC tissue microarrays. The Cell Counting Kit-8, colony formation assay, 5-ethynyl-2'-deoxyuridine assay, transwell assays, wound-healing assays, and flow cytometry assessed the role of IGF2BP3 in proliferation and metastasis of CC cells. Besides, exploring the molecular mechanism participating in IGF2BP3-driven lipid metabolism used RNA-seq, which determined SCD as the target of IGF2BP3. Further, lipid droplets, cellular triglyceride (TG) contents, and fatty acids were accessed to discover that IGF2BP3 can enhance lipid metabolism in CC. Moreover, RIP assay and methylated RNA immunoprecipitation experiments seeked the aimed-gene-binding specificity. Lastly, the IGF2BP3 knockdown restrained CC growth and lipid metabolism, after which SCD overexpression rescued the influence in vitro and in vivo using nude mouse tumor-bearing model. Mechanistically, IGF2BP3 regulated SCD mRNA m6A modifications via IGF2BP3-METTL14 complex, thereby enhanced CC proliferation, metastasis, and lipid metabolism. Our study highlights IGF2BP3 plays a crucial role in CC progression and represents a therapeutic latent strategy. It is a potential tactic that blocks the metabolic pathway relevant to IGF2BP3 with the purpose of treating CC.
Assuntos
Neoplasias do Colo do Útero , Animais , Feminino , Humanos , Camundongos , Linhagem Celular Tumoral , Proliferação de Células/genética , Metabolismo dos Lipídeos/genética , Neoplasias do Colo do Útero/patologiaRESUMO
BACKGROUND: In recent years, there have been breakthroughs in the preclinical research of respiratory diseases, such as organoids and organ tissue chip models, but they still cannot provide insight into human respiratory diseases well. Human lung slices model provides a promising in vitro model for the study of respiratory diseases because of its preservation of lung structure and major cell types. METHODS: Human lung slices were manually prepared from small pieces of lung tissues obtained from lung cancer patients subjected to lung surgery. To evaluate the suitability of this model for lung fibrosis research, lung slices were treated with CdCl2 (30 µM), TGF-ß1 (1 ng/ml) or CdCl2 plus TGF-ß1 for 3 days followed by toxicity assessment, gene expression analysis and histopathological observations. RESULTS: CdCl2 treatment resulted in a concentration-dependent toxicity profile evidenced by MTT assay as well as histopathological observations. In comparison with the untreated group, CdCl2 and TGF-ß1 significantly induces MMP2 and MMP9 gene expression but not MMP1. Interestingly, CdCl2 plus TGF-ß1 significantly induces the expression of MMP1 but not MMP2, MMP7 or MMP9. Microscopic observations reveal the pathogenesis of interstitial lung fibrosis in the lung slices of all groups; however, CdCl2 plus TGF-ß1 treatment leads to a greater alveolar septa thickness and the formation of fibroblast foci-like pathological features. The lung slice model is in short of blood supply and the inflammatory/immune-responses are considered minimal. CONCLUSIONS: The results are in favor of the hypothesis that idiopathic pulmonary fibrosis (IPF) is mediated by tissue damage and abnormal repair. Induction of MMP1 gene expression and fibroblast foci-like pathogenesis suggest that this model might represent an early stage of IPF.
Assuntos
Fibrose Pulmonar Idiopática , Fator de Crescimento Transformador beta1 , Humanos , Fator de Crescimento Transformador beta1/genética , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Pulmão/patologia , Fibroblastos/metabolismoRESUMO
BACKGROUND: The crosstalk between the ubiquitin-proteasome and the immune system plays an important role in the health and pathogenesis of viral infection. However, there have been few studies of ubiquitin activation in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. METHODS: We investigated the effect of ubiquitination on SARS-CoV-2 infection and patient prognosis by integrating published coronavirus disease 2019 (COVID-19) multi-transcriptome data and bioinformatics methods. RESULTS: The differential expression of COVID-19 samples revealed changed ubiquitination in most solid and hollow organs, and it was activated in lymphatic and other immune tissues. In addition, in the respiratory system of COVID-19 patients, the immune response was mainly focused on the alveoli, and the expression of ubiquitination reflected increasing immune infiltration. Ubiquitination stratification could significantly differentiate patients' prognosis and inflammation levels through the general transcriptional analysis of the peripheral blood of patients with COVID-19. Moreover, high ubiquitination levels were associated with a favourable prognosis, low inflammatory response, and reduced mechanical ventilation and intensive care unit. Moreover, high ubiquitination promoted a beneficial immune response while inhibiting immune damage. Finally, prognostic stratification and biomarker screening based on ubiquitination traits played an important role in clinical management and drug development. CONCLUSION: Ubiquitination characteristics provides new ideas for clinical intervention and prognostic guidance for COVID-19 patients.
Assuntos
COVID-19 , SARS-CoV-2 , Humanos , SARS-CoV-2/genética , COVID-19/genética , Ubiquitinação/genética , Ubiquitina , Complexo de Endopeptidases do ProteassomaRESUMO
Background: Increasing evidence shows that the ubiquitin-proteasome system has a crucial impact on lung adenocarcinoma. However, reliable prognostic signatures based on ubiquitination and immune traits have not yet been established. Methods: Bioinformatics was performed to analyze the characteristic of ubiquitination in lung adenocarcinoma. Principal component analysis was employed to identify the difference between lung adenocarcinoma and adjacent tissue. The ubiquitin prognostic risk model was constructed by multivariate Cox regression and least absolute shrinkage and selection operator regression based on the public database The Cancer Genome Atlas, with evaluation of the time-dependent receiver operating characteristic curve. A variety of algorithms was used to analyze the immune traits of model stratification. Meanwhile, the drug response sensitivity for subgroups was predicted by the "pRRophetic" package based on the database of the Cancer Genome Project. Results: The expression of ubiquitin genes was different in the tumor and in the adjacent tissue. The ubiquitin model was superior to the clinical indexes, and four validation datasets verified the prognostic effect. Additionally, the stratification of the model reflected distinct immune landscapes and mutation traits. The low-risk group was infiltrating plenty of immune cells and highly expressed major histocompatibility complex and immune genes, which illustrated that these patients could benefit from immune treatment. The high-risk group showed higher mutation and tumor mutation burden. Integrating the tumor mutation burden and the immune score revealed the patient's discrepancy between survival and drug response. Finally, we discovered that the drug targeting ubiquitin and proteasome would be a beneficial prospective treatment for lung adenocarcinoma. Conclusion: The ubiquitin trait could reflect the prognosis of lung adenocarcinoma, and it might shed light on the development of novel ubiquitin biomarkers and targeted therapy for lung adenocarcinoma.
Assuntos
Adenocarcinoma de Pulmão , Neoplasias Pulmonares , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Biomarcadores Tumorais/genética , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/patologia , Estudos Prospectivos , Complexo de Endopeptidases do Proteassoma/genética , Complexo de Endopeptidases do Proteassoma/metabolismo , Transcriptoma , Ubiquitinação , Ubiquitinas/metabolismoRESUMO
Enhanced aerobic glycolysis constitutes an additional source of energy for tumor proliferation and metastasis. Human papillomavirus (HPV) infection is the main cause of cervical cancer (CC); however, the associated molecular mechanisms remain poorly defined, as does the relationship between CC and aerobic glycolysis. To investigate whether HPV 16/18 E6/E7 can enhance aerobic glycolysis in CC, E6/E7 expression was knocked down in SiHa and HeLa cells using small interfering RNA (siRNA). Then, glucose uptake, lactate production, ATP levels, reactive oxygen species (ROS) content, extracellular acidification rate (ECAR) and oxygen consumption rate (OCR) were evaluated. RNA-seq was used to probe the molecular mechanism involved in E6/E7-driven aerobic glycolysis, and identified IGF2BP2 as a target of E6/E7. The regulatory effect of IGF2BP2 was confirmed by qRT-PCR, western blot, and RIP assay. The biological roles and mechanisms underlying how HPV E6/E7 and IGF2BP2 promote CC progression were confirmed in vitro and in vivo. Human CC tissue microarrays were used to analyze IGF2BP2 expression in CC. The knockdown of E6/E7 and IGF2BP2 attenuated the aerobic glycolytic capacity and growth of CC cells, while IGF2BP2 overexpression rescued this effect in vitro and in vivo. IGF2BP2 expression was higher in CC tissues than in adjacent tissues and was positively correlated with tumor stage. Mechanistically, E6/E7 proteins promoted aerobic glycolysis, proliferation, and metastasis in CC cells by regulating MYC mRNA m6A modifications through IGF2BP2. We found that E6/E7 promote CC by regulating MYC methylation sites via activating IGF2BP2 and established a link between E6/E7 and the promotion of aerobic glycolysis and CC progression. Blocking the HPV E6/E7-related metabolic pathway represents a potential strategy for the treatment of CC.
Assuntos
Proteínas de Ligação a DNA/genética , Proteínas Oncogênicas Virais/genética , Proteínas E7 de Papillomavirus/genética , Proteínas de Ligação a RNA/genética , Proteínas Repressoras/genética , Neoplasias do Colo do Útero/patologia , Efeito Warburg em Oncologia , Animais , Linhagem Celular Tumoral , Proliferação de Células , Feminino , Terapia Genética , Papillomavirus Humano 16/genética , Papillomavirus Humano 18/genética , Humanos , Metiltransferases/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Infecções por Papillomavirus/virologia , Proteínas Proto-Oncogênicas c-myc/metabolismo , RNA Mensageiro/genética , RNA Interferente Pequeno/genética , Neoplasias do Colo do Útero/virologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Worldwide, lung cancer remains a leading cause of cancer mortality. Bruceine D (BD) has been shown to induce pancreatic cancer cell death via several different mechanisms. In this study, we demonstrated that BD inhibited lung cancer cell proliferation. Apoptosis and autophagy were the most important mechanisms involved in BD-induced lung cancer cell death, and complete autophagic flux was observed in A549 and NCI-H292 cells. In addition, BD significantly improved intracellular reactive oxygen species (ROS) levels. BD-mediated cell apoptosis and autophagy were almost inhibited in cells pretreated with N-acetylcysteine (NAC), an ROS scavenger. Furthermore, MAPK signaling pathway activation contributed to BD-induced cell proliferation inhibition and NAC could eliminate p-ERK and p-JNK upregulation. Finally, an in vivo study indicated that BD inhibited the growth of lung cancer xenografts. Overall, BD is a promising candidate for the treatment of lung cancer owing to its multiple mechanisms and low toxicity.