BCL2Family of Apoptosis-Related Genes: Functions and Clinical Implications in Cancer

Abstract

One of the most effective ways to combat different types of cancer is through early diagnosis and administration of effective treatment, followed by efficient monitoring that will allow physicians to detect relapsing disease and treat it at the earliest possible time. Apoptosis, a normal physiological form of cell death, is critically involved in the regulation of cellular homeostasis. Dysregulation of programmed cell death mechanisms plays an important role in the pathogenesis and progression of cancer as well as in the responses of tumours to therapeutic interventions. Many members of the BCL2 (B-cell CLL/lymphoma 2; Bcl-2) family of apoptosis-related genes have been found to be differentially expressed in various malignancies, and some are useful prognostic cancer biomarkers. We have recently cloned a new member of this family, BCL2L12, which was found to be differentially expressed in many tumours. Most of the BCL2 family genes have been found to play a central regulatory role in apoptosis induction. Results have made it clear that a number of coordinating alterations in the BCL2 family of genes must occur to inhibit apoptosis and provoke carcinogenesis in a wide variety of cancers. However, more research is required to increase our understanding of the extent to which and the mechanisms by which they are involved in cancer development, providing the basis for earlier and more accurate cancer diagnosis, prognosis and therapeutic intervention that targets the apoptosis pathways. In the present review, we describe current knowledge of the function and molecular characteristics of a series of classic but also newly discovered genes of the BCL2 family as well as their implications in cancer development, prognosis and treatment.

Pancreatic cancer cells resistance to gemcitabine: the role of MUC4 mucin

“…No difference was observed in Bad protein levels between CD18/HPAF/Scr and CD18/HPAF/siMUC4 cells ( Figure 3A). MUC1 and rat Muc4 has been shown to decrease apoptosis in response to various insults also by enhancing the expression of Bcl-X L (Raina et al, 2006;Thomadaki and Scorilas, 2006;Workman et al, 2009). In contrast, we did not observe any difference in Bcl-X L protein levels after gemcitabine treatment of CD18/HPAF/Scr and CD18/HPAF/siMUC4 cells (data not shown).…”

“…Phosphorylation of Bad promotes its interaction with the scaffolding protein 14-3-3 and prevents its interaction with antiapoptotic Bcl-X L protein, leading to its sequestration in the cytosol and inhibition of its pro-apoptotic activity (Thomadaki and Scorilas, 2006). We found that MUC4 increases phosphorylation of Bad in CD18/HPAF/Scr cells in response to gemcitabine treatment.…”

“…No change was observed in the expression of anti-apoptotic protein Bcl-X L , which has been shown to be a major player in the inhibition of intrinsic apoptotic pathway in response to various insults in earlier studies. The mitochondrialassociated anti-apoptotic proteins Bcl-2 and Bcl-X L suppress intrinsic mitochondrial apoptotic pathway, whereas pro-apoptotic proteins, such as Bad, translocate to mitochondria in response to apoptotic signals, and interact with and deactivate Bcl-2 and Bcl-X L (Yang et al, 1995;Thomadaki and Scorilas, 2006). The proapoptotic activity of Bad is suppressed by its phosphorylation on serine residues in response to survival signalling cascades.…”

Apoptosis Gene Network Regulated by Delta-Tocotrienol in K562 Chronic Myeloid Leukaemia Cells

“…The intrinsic pathway is mediated by the mitochondria, and the BCL2 family of genes are central to regulating this mode of apoptosis (Thomadaki and Scorilas, 2006). Delta-tocotrienoltreatment of K562 cells induced the expression of several members of this family, namely the BAD, BCL2L1, BNIP3L, HRK and MCL1 genes.…”

Melanoma in Immunosuppressed Patients

“…[62][63][64][65][66] Specifically, 95% of patients with CLL have overexpression of BCL-2, which may explain why these patients have lymphocytes with increased longevity. 67 Interestingly, 90% of melanoma patients also have elevated BCL-2 levels, which could be a contributing factor in why some melanoma patients seem to have treatment resistance, with melanoma cells capable of escaping immunosurveillance. 68,69 Another mutation commonly found in the CLL population is deletion of 17p, which is where the TP53 gene is found.…”