BCL‐2 family proteins: Regulators of cell death involved in the pathogenesis of cancer and resistance to therapy

Abstract

The BCL-2 gene was first discovered because of its involvement in the t(14;18) chromosomal translocations commonly found in lymphomas, which result in deregulation of BCL-2 gene expression and cause inappropriately high levels of Bcl-2 protein production. Expression of the BCL-2 gene can also become altered in human cancers through other mechanisms, including loss of the p53 tumor suppressor which normally functions as a repressor of BCL-2 gene expression in some tissues. Bcl-2 is a blocker of programmed cell death and apoptosis that contributes to neoplastic cell expansion by preventing cell turnover caused by physiological cell death mechanisms, as opposed to accelerating rates of cell division. Overproduction of the Bcl-2 protein also prevents cell death induced by nearly all cytotoxic anticancer drugs and radiation, thus contributing to treatment failures in patients with some types of cancer. Several homologs of Bcl-2 have recently been discovered, some of which function as inhibitors of cell death and others as promoters of apoptosis that oppose the actions of the Bcl-2 protein. Many of these Bcl-2 family proteins can interact through formation of homo- and heterotypic dimers. In addition, several nonhomologous proteins have been identified that bind to Bcl-2 and that can modulate apoptosis. These protein-protein interactions may eventual serve as targets for pharmacologically manipulating the physiological cell death pathway for treatment of cancer and several other diseases.

Overexpression of hRFI inhibits 5-fluorouracil-induced apoptosis in colorectal cancer cells via activation of NF-κB and upregulation of BCL-2 and BCL-XL

“…Evidence indicates that Bcl-2 and Bcl-XL act as stabilizers of mitochondrial membrane integrity by blocking the release of cytochrome c and subsequent caspase-9 and -3 activation, thus regulating the mitochondrial apoptotic pathway (Korsmeyer, 1992;Kluck et al, 1997;Martinou et al, 2000;Tsujimoto, 2000;. These effects comprise the main mechanism by which Bcl-2 and Bcl-XL inhibit the induction of apoptosis by a variety of chemotherapeutic agents hRFI enhances chemoresistance to 5-FU T Konishi et al including 5-FU (Miyashita and Reed, 1993;Reed et al, 1996;Nita et al, 2000;Sun et al, 2002;Violette et al, 2002). In compatible with this evidence, the present study has revealed that siRNA downregulation of either Bcl-2 or Bcl-XL prominently increases 5-FU-induced apoptosis, indicating that both Bcl-2 and Bcl-XL are crucial determinants of the apoptosis sensitivity towards 5-FU in HCT116 cells.…”

The prognostic influence of bcl-2 in malignant glioma

“…In neuroblastoma bcl-2 expression seems to correlate with the morphology and differentiation of neuroblastoma cells in vitro, greater bcl-2 expression being associated with more neuroblastic cells (Reed et al, 1991). Studies in, for example, myeloid leukaemia, carcinoma of prostate and large cell Non Hodgkins lymphoma, have found bcl-2 expression to be associated with a poor response to treatment, and a shorter disease free and overall survival (Colombel, 1993;Reed et al, 1996). However, Silvestrini et al (1994), found bcl-2 expression to correlate with a good prognosis in breast cancer.…”

“…However, Silvestrini et al (1994), found bcl-2 expression to correlate with a good prognosis in breast cancer. Reed et al (1996) discussed this paradoxical result, hypothesising that it is a reflection of the complex interaction between the family of genes which control apoptosis, and in particular the ratio of activity of the proapoptotic gene Bax to the anti apoptotic bcl-2. A decrease in the ratio of bcl-2 to Bax protein renders cells more vulnerable to apoptosis (Borner, 1996).…”

“…P53 acts to cause this effect and other members of the bcl-2 family also act in concert. Reed et al (1996) suggest that in Silvestrini's group of patients reductions in bcl-2 were tolerated because of diminished Bax protein, keeping the ratio in favour of apoptosis, and conferring a good prognosis. Krawejski et al (1995) showed that loss of BAX expression was strongly associated with loss of bcl-2 immunopositivity in a small group of metastatic breast cancer patients.…”

Differential chemosensitivity of breast cancer cells to ganciclovir treatment following adenovirus-mediated herpes simplex virus thymidine kinase gene transfer

“…However, results to date indicate that members of the Bcl-2 family of proteins play a prominent role in regulating intracellular thresholds to apoptotic cell death-promoting stimuli. 87 Bcl-2 functions as a negative regulator of apoptosis and has been reported to be overexpressed in Յ70% of breast cancers. 88 Furthermore, high levels of bcl-2 gene expression have been correlated with an increased resistance to therapeutic agents that activate both p53-dependent and -independent apoptotic signaling pathways.…”