Gelidiella acerosa Compounds Target NFκB Cascade in Lung Adenocarcinoma.

In carcinogenesis, increased metabolism, abnormal functioning of mitochondria, peroxisomes, aberrant cell signaling, and prolonged inflammation can result in the overproduction of reactive oxygen species (ROS). In turn, excess ROS can upregulate the expression of various signaling pathways including the MAP kinase, PI3K/Akt, and NFκB cascades in cancer. The constitutive expression of NFκB causes drug resistance in lung cancer. Hence, drugs that can enhance the antioxidant activity of enzymes and regulate the NFκB activity are of prime target to manage the drug resistance and inflammation in cancer. This study evaluated the effect of compounds present in ethyl acetate extract of Gelidiella acerosa on inflammation and on antioxidant enzymes in lung cancer. The anti-inflammatory activity was determined under in silico and in vitro conditions. The in silico analysis showed that the phyto-constituents of G. acerosa inhibit the IKBα-NFκB-p65-p50 complex in a similar way as that of doxorubicin and dexamethasone. Similarly, G. acerosa treatment enhanced the efficiency of antioxidant enzymes peroxidases and superoxide dismutase in A549 lung cancer cells. Furthermore, the results of in vitro analysis showed that G. acerosa can decrease the activation of NFκB and production of pro-inflammatory cytokines and upregulate the expression of IL 10. As inflammation causes cancer progression, the inhibition of inflammation inhibits tumorigenesis. Hence, based on the results of the study, it can be concluded that G. acerosa exerts anti-inflammatory activity by decreasing the expression of NFκB cascade and moreover, the phyto-constituents of G. acerosa may have the potential to regulate the inflammatory response.

Identification of canonical NFκB (C-NFκB) pathway in uveal melanoma and their relation with patient outcome.

Inflammation in uveal melanoma (UM) is linked to a bad prognosis. It is rare type of cancer, of which the metastases are usually fatal within a year. Infiltration with an inflammatory infiltrate increases with disease progression but does not seem to inhibit metastasis. The Canonical NFκB (C-NFκB) pathway is known to play a crucial role in tumor inflammation. We therefore, studied the expression of canonical NFκB proteins and their prognostic relevance in UM. Our study evaluated the expression of C-NFκB proteins (p65, p50, and c-Rel) by using immunohistochemistry on sections from 75 formalin-fixed UM. Activation of the NFκB subunit was determined on fresh tumor specimens by measuring the DNA-binding activity in nuclei using an NFκB ELISA assay. Real-time PCR was performed on frozen material on 58 tumors. The presence of native C-NFκB heterodimers (p65/p50 and c-Rel/p50) was confirmed by co-immunoprecipitation followed by Western blotting. We observed a high nuclear immunoreactivity of p65, p50, and c-Rel proteins in 54, 60 and 41% UM cases, respectively. Expression of C-NFκB proteins significantly correlated with parameters which are related to the inflammatory environment of UM. Nuclear immunoreactivity of p65 and p50 was associated with lower patient survival (p = 0.041; p = 0.048) while c-Rel was not. Our finding reveals that C-NFκB proteins expressed are more often in UM with inflammation than those without inflammation. Activation of the canonical NFκB pathway is more frequent in high risk UM patients. These observations might help to understand the behaviour of high risk tumors, with upregulation of C-NFκB proteins contributing to tumor aggressiveness.

Aldosterone-induced expression of ENaC-α is associated with activity of p65/p50 in renal epithelial cells.

The amiloride-sensitive epithelial sodium channel (ENaC), located in the apical membrane in the cortical collecting duct of the kidney, mediates the fine-tuned regulation of external Na+ balance. Expression of the alpha-subunit of ENaC (ENaC-α) is regulated by a number of factors in the lung, including transcription factor nuclear factor kappa B (NF-κB). In the present study, we examined the effect of IKKß/p65/p50 on ENaC-α in a murine cortical collecting duct cell line that endogenously expresses ENaC, mpkCCDc14 (CCD) cells. Aldosterone exposure led to up-regulation of ENaC-α and IKKß, and nuclear p65 and p50. Knockdown of IKKß or p65 exhibited >60 % reduction of aldosterone-induced ENaC-α mRNA levels. Chromatin immunoprecipitation and electrophoretic mobility shift assays demonstrated a specific interaction between p65/p50 and ENaC-α gene promoter, which was further confirmed using luciferase reporter-gene vectors transiently transfected into CCD cells. Taken together these data support an important role for p65/p50 in the direct regulation of ENaC-α transcription and have important implications for understanding the role of NF-κB in the regulation of renal function.

Alteration of Apoptotic Regulatory Molecules in Conventional Renal Cell Carcinoma Influenced by Chronic Long-term Low-dose Ionizing Radiation Exposure in Humans Revealed by Tissue Microarray.

Compared to the 19-year period subsequent to the Chernobyl accident, the morbidity of malignant renal tumors in the Ukraine has increased from 4.7 to 9.0 per 100,000 of the total population. Cesium 137 (137Cs), which accounts for 90% of the internal radioactivity in the Ukrainian population exposed to long-term low-dose radiation and 90% of the more labile pool of 137Cs, is excreted via the kidneys. Our present study aimed to evaluate the status of pro- and anti-apoptotic regulatory molecules in conventional renal cell carcinomas (cRCCs) in Ukrainian patients. To achieve this objective, Bcl-2, Bcl-x, BAX, death receptor (DR5) and transcriptional nuclear factor kappa B (NF-κB, with p50 and p65 subunits) were immunohistochemically investigated using a tissue microarray technique in cRCCs from a group of 56 Ukrainian patients, comprising 18 patients living in non-contaminated areas and 41 patients from 137Cs-contaminated areas. As a comparison, 19 Spanish patients with analogous tumors were also investigated. It was shown that BAX and DR5-positive cRCCs tended to increase among the Ukrainian patients living in the radio-contaminated areas, along with the suppression of anti-apoptotic molecules (Bcl-2 and Bcl-x) and with p65 and p50 overexpression in the same tumors. This study suggested that chronic long-term, low-dose radiation exposure might result in the alteration of the apoptotic regulatory mechanisms, which, in turn, could lead to enhanced tumor progression and resistance to apoptosis.