CommentaryRole of Bcl-2 and its post-transcriptional modification in response to antitumor therapy
Introduction
Apoptosis has received much attention, because this form of cell death seems to be the predominant cellular response to effective antitumor treatment [1], [2]. Thus, susceptibility to drug-induced apoptosis is recognized as a critical determinant of tumor cell sensitivity to antitumor agents. Although drug resistance of tumor cells may involve multiple factors, there is evidence to support the hypothesis that cancer cells can exhibit resistance to cytotoxic agents as a result of alterations of apoptosis-related proteins [1], [3]. The ability of the cell to undergo apoptosis and the threshold at which a specific cell injury triggers the process critically influence drug efficacy and the therapeutic index of drug treatment.
At least three functionally distinct phases of apoptotic cell death have been identified [4]. The biochemical pathway of the initiation phase depends on the nature of the lethal stimulus (receptor- or stress-mediated induction). The downstream events (effector and degradation phases) involve regulatory gene products (including activators and repressors) that modulate the apoptotic response. Among the known genes that regulate apoptosis induced by a wide variety of cytotoxic stimuli, the Bcl-2 gene family plays an important role [5]. The gene products of the Bcl-2 family include a number of proteins, characterized by amino acid sequence homology [4], that have been implicated in regulating the effector stage of the apoptotic pathway. Like Bcl-2, some members act by inhibiting apoptotic cell death. An opposite (proapoptotic) function has been described for other Bcl-2-related proteins (e.g. Bax and Bad). Bcl-2 was originally found in human B-cell lymphomas in which it becomes deregulated as a result of chromosomal translocation [6].
Since high levels of Bcl-2 expression have been detected in a variety of tumor types, additional mechanisms, besides chromosomal translocations, appear to be involved in the deregulation of Bcl-2 expression. In particular, a negative regulation of Bcl-2 transcription by the p53 tumor suppressor gene has been reported [6]. Since loss of p53 function following mutation is a very common alteration in human tumors, the finding of Bcl-2 up-regulation in a large variety of tumors is not surprising. On the basis of its overexpression and antiapoptotic function, Bcl-2 has been implicated in drug resistance [3], [6]. Protection by Bcl-2 and related antiapoptotic proteins against cell death induced by a variety of antitumor agents has been proposed as a novel mechanism of multidrug resistance [6]. In spite of the complex and controversial mechanism of apoptosis regulation by the Bcl-2 family protein [5], an obvious possible therapeutic intervention to overcome resistance to apoptosis is the manipulation of the Bcl-2-mediated control system, since the function of Bcl-2-related proteins resides at a critical step upstream of irreversible cellular damage (i.e. caspase activation) [4].
Section snippets
Bcl-2 and drug resistance
Based on the well-established role of Bcl-2 as a critical regulator of the cell death process, overexpression of this protein is expected to confer a relative resistance to the cytotoxic effects of antitumor therapies. However, despite the functional importance of Bcl-2 and related proteins in apoptosis control, the relationship between Bcl-2 expression and drug resistance of tumor cells remains controversial. Much of the confusion may be related to the complex regulation of the apoptotic
Regulation of Bcl-2 function
Since the cellular response following a cytotoxic injury is dependent on a complex decision that involves coordinated signal transduction pathways affecting the cell death machinery, it is evident that the alteration of a single regulatory component, like Bcl-2, is not sufficient to determine the final outcome. Even among leukemia cells, there is evidence that Bcl-2 expression may not be effective in suppressing apoptosis in all circumstances [27]. Lack of cell protection by elevated levels of
Conclusions
The evidence that survival genes may be deregulated in tumors [3] and the better understanding of their role in the mechanism of apoptosis regulation have provided new insights to develop therapeutic strategies aimed at enhancing cellular susceptibility to drug-induced apoptosis and improving the therapeutic index of cytotoxic therapy. The identification of the biological context in which Bcl-2 may confer a relative resistance to apoptosis induction is expected to better define the therapeutic
Acknowledgements
This work was partially supported by the Associazione Italiana per la Ricerca sul Cancro, Milan, and by the Ministero della Sanita’, Roma, Italy.
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