RESUMEN
Many challenges are faced in pancreatic cancer treatment due to late diagnosis and poor prognosis because of high recurrence and metastasis. Extracellular vesicles (EVs) and matrix metalloproteinases (MMPs), besides acting in intercellular communication, are key players in the cancer cell plasticity responsible for initiating metastasis. Therefore, these entities provide valuable targets for the development of better treatments. In this context, this study aimed to evaluate the potential of calix[6]arene to disturb the release of EVs and the activity of MMPs in pancreatic cancer cells. We found a correlation between the endocytic-associated mediators and the prognosis of pancreatic cancer patients. We observed a more active EV machinery in the pancreatic cancer cell line PANC-1, which was reduced three-fold by treatment with calix[6]arene at subtoxic concentration (5 µM; p ã0,001). We observed the modulation of 186 microRNAs (164 miRNAs upregulated and 22 miRNAs downregulated) upon calix[6]arene treatment. Interestingly, some of them as miR-4443 and miR-3909, regulates genes HIF1A e KIF13A that are well known to play a role in transport of vesicles. Furthermore, Calix[6]arene downmodulated matrix metalloproteinases (MMPs) -2 and - 9 and disturbed the viability of pancreatic organoids which recapitulate the cellular heterogeneity, structure, and functions of primary tissues. Our findings shed new insights on calix[6]arene's antitumor mechanism, including its intracellular effects on vesicle production and trafficking, as well as MMP activity, which may harm the tumor microenvironment and contribute to a reduction in cancer cell dissemination, which is one of the challenges associated with high mortality in pancreatic cancer.
Asunto(s)
Calixarenos , Vesículas Extracelulares , MicroARNs , Neoplasias Pancreáticas , Fenoles , Humanos , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/tratamiento farmacológico , Calixarenos/farmacología , Vesículas Extracelulares/metabolismo , Línea Celular Tumoral , Fenoles/farmacología , MicroARNs/metabolismo , MicroARNs/genética , Regulación Neoplásica de la Expresión Génica/efectos de los fármacosRESUMEN
Chemotherapy resistance is one of the main challenges in melanoma treatment. Violacein, a natural pigment produced by Chromobacterium violaceum, induces apoptosis in a variety of tumours, including melanoma. Here, we used BRAF-mutated melanoma spheroids to test the potential of violacein as a sensitizer of cellular viability and levels of the proteins p62 and fatty acid synthase (FASN). Importantly, violacein in combination with vemurafenib (ViVe) was able to interfere with spheroid survival at subtoxic concentrations. The results demonstrated that the ViVe protocol triggered cell death assessed by calcein and ethidium homodimer dyes. Accordingly, melanoma cells in 2D systems also showed a higher apoptosis rate when treated with ViVe. In the current study, we show evidence that ViVe downregulates crucial mediators like FASN, which partially explains how it acts as a sensitizer and ultimately improves the effectiveness of vemurafenib against melanoma cells.
RESUMEN
The main post-translational reversible modulation of proteins is phosphorylation and dephosphorylation, catalyzed by protein kinases (PKs) and protein phosphatases (PPs) which is crucial for homeostasis. Imbalance in this crosstalk can be related to diseases, including cancer. Plenty of evidence indicates that protein tyrosine phosphatases (PTPs) can act as tumor suppressors and tumor promoters. In gastric cancer (GC), there is a lack of understanding of the molecular aspects behind the tumoral onset and progression. Here we describe several members of the PTP family related to gastric carcinogenesis. We discuss the associated molecular mechanisms which support the down or up modulation of different PTPs. We emphasize the Helicobacter pylori (H. pylori) virulence which is in part associated with the activation of PTP receptors. We also explore the involvement of intracellular redox state in response to H. pylori infection. In addition, some PTP members are under influence by genetic mutations, epigenetics mechanisms, and miRNA modulation. The understanding of multiple aspects of PTPs in GC may provide new targets and perspectives on drug development.
Asunto(s)
Proteínas Tirosina Fosfatasas/metabolismo , Neoplasias Gástricas/metabolismo , Helicobacter pylori/enzimología , Humanos , Procesamiento Proteico-Postraduccional , Proteínas Tirosina Fosfatasas/genética , ARN Mensajero/genética , ARN Mensajero/metabolismo , Neoplasias Gástricas/diagnósticoRESUMEN
BACKGROUND: Expression of matrix metalloproteases 2, 9 and 14 (MMP-2, MMP-9, MMP-14), tissue inhibitors of metalloprotease 1 and 2 (TIMP-1, TIMP-2) and vascular endothelial growth factor A (VEGF-A) is involved in tumor invasion and metastasis via extracellular matrix degradation and angiogenesis. This study aimed to assess whether the expression of MMP-2, MMP-9, MMP-14, TIMP-1, and TIMP-2 in tumors and in the adjacent stroma is associated with cervical cancer prognosis. METHODS: This study analyzed a retrospective cohort of 64 patients. Protein expression was previously obtained by immunohistochemistry from biopsies containing both tumor and stroma. The expression and percentage of stained cells were categorized as high or low according to the cutoff points by using ROC curves. The follow-up data was collected from diagnosis to the last clinical visit. Clinical status categorized as alive without disease, alive with disease, death due to other causes, and death from the disease. The relative risk of death from the disease was evaluated according to the proteins expression using a cause-specific Cox regression model with a 95% confidence interval (95%CI). For the significant associations (p < 0.05), survival curves of patients with low and high expression were plotted for the competing risk survival curve analyses. RESULTS: High expression levels of stromal MMP-2 (RR; 95%CI: 3.91; 1.17-13.02) and stromal TIMP-2 (RR, 95%CI: 8.67; 1.15-65.27) were associated with a greater relative risk of death from the disease and with lower survival (p = 0.03; p = 0.04) than lower expression levels. Low expression levels of stromal MMP-9 (RR, 95%CI: 0.19; 0.05-0.65) and tumoral MMP-9 (HR, 95%CI: 0.19; 0.04-0.90) were protective factors against death from the disease and were associated with poorer survival. CONCLUSIONS: High expression levels of MMP-2 and TIMP-2 in the stroma were significantly associated with poor survival in cervical cancer patients. High expression of MMP-9 was associated with a favorable cervical cancer prognosis.