BAD-mediated apoptotic pathway is associated with human cancer development

Abstract

The malignant transformation of normal cells is caused in part by aberrant gene expression disrupting the regulation of cell proliferation, apoptosis, senescence and DNA repair. Evidence suggests that the Bcl-2 antagonist of cell death (BAD)-mediated apoptotic pathway influences cancer chemoresistance. In the present study, we explored the role of the BAD-mediated apoptotic pathway in the development and progression of cancer. Using principal component analysis to derive a numeric score representing pathway expression, we evaluated clinico-genomic datasets (n=427) from corresponding normal, pre-invasive and invasive cancers of different types, such as ovarian, endometrial, breast and colon cancers in order to determine the associations between the BAD-mediated apoptotic pathway and cancer development. Immunofluorescence was used to compare the expression levels of phosphorylated BAD [pBAD (serine-112, -136 and -155)] in immortalized normal and invasive ovarian, colon and breast cancer cells. The expression of the BAD-mediated apoptotic pathway phosphatase, PP2C, was evaluated by RT-qPCR in the normal and ovarian cancer tissue samples. The growth-promoting effects of pBAD protein levels in the immortalized normal and cancer cells were assessed using siRNA depletion experiments with MTS assays. The expression of the BAD-mediated apoptotic pathway was associated with the development and/or progression of ovarian (n=106, p<0.001), breast (n=185, p<0.0008; n=61, p=0.04), colon (n=22, p<0.001) and endometrial (n=33, p<0.001) cancers, as well as with ovarian endometriosis (n=20, p<0.001). Higher pBAD protein levels were observed in the cancer cells compared to the immortalized normal cells, whereas PP2C gene expression was lower in the cancer compared to the ovarian tumor tissue samples (n=76, p<0.001). The increased pBAD protein levels after the depletion of PP2C conferred a growth advantage to the immortalized normal and cancer cells. The BAD-mediated apoptotic pathway is thus associated with the development of human cancers likely influenced by the protein levels of pBAD.

Oxidative Stress-Induced DNA Damage and Apoptosis in Clove Buds-Treated MCF-7 Cells

“…In the present study, a significant increase of total Bad in CBE-treated cells was found. It is broadly accepted that only non-phosphorylated Bad may block anti-apoptotic Bcl-xL and Bcl-2 proteins, release pro-apoptotic Bax and initiate MOM permeability [27]. However, the experiments presented here showed increased levels of phosphorylated Bad after 24 h of treatment with a subsequent decrease of phosphorylation to control levels after 48 and 72 h of incubation (Figure 1 D,E).…”

Comparative transcriptome analysis of Eriocheir japonica sinensis response to environmental salinity

“…These results were consistent with those of Hui et al (2014), who performed a desalination-based transcriptome analysis on larvae of Chinese mitten crabs. Membrane permeability is related to osmoregulation [ 60 ]; for this reason, up-regulation of 14-3-3 epsilon protein may have an important role in osmoregulation because the 14-3-3 epsilon protein could suppress activation of Bcl-2, an antagonist of cell death, and further stop initiating mitochondrial membrane permeability [ 61 ]. Moreover, transporters are important osmoregulation factors responsible for the uptake and efflux of important substances such as inorganic ions, sugars and amino acids.…”

BCL-2 family deregulation in colorectal cancer: potential for BH3 mimetics in therapy

“…Therefore, this increased expression could indicate the presence of compensatory mechanisms that enable tumor cells to override such selection pressures. PTMs that deregulate BH3-only proteins are also reported in CRC such as an increase in BAD phosphorylation, which attenuates BAD pro-apoptotic activity and facilitates tumorigenesis [106,134,135].…”