Elsevier

Biochemical Pharmacology

Volume 61, Issue 4, 15 February 2001, Pages 381-386
Biochemical Pharmacology

Commentary
Role of Bcl-2 and its post-transcriptional modification in response to antitumor therapy

https://doi.org/10.1016/S0006-2952(00)00538-4Get rights and content

Abstract

Bcl-2 blocks or delays apoptosis in many cell systems. The protein exerts its antiapoptotic effect mainly in the membrane of mitochondria. Indeed, emerging evidence supports that the mitochondrion plays an important role in the cell death pathway, integrating different pro- and antiapoptotic stimuli. Since deregulation of the expression of Bcl-2 occurs in a variety of human tumors, modulation of its function is regarded as an exploitable manipulation for pharmacological intervention in antitumor chemotherapy. Phosphorylation of Bcl-2 has been implicated as an important regulatory mechanism of its function and is a common event in response to antimitotic drugs. Recently, a similar post-transcriptional modification was observed in response to DNA-damaging agents in some tumor systems, but this is not a general finding in response to genotoxic drugs. Current investigations indicate that different signaling pathways may be involved in Bcl-2 phosphorylation, likely dependent on the kinases activated by the various stress stimuli. A better understanding of the molecular mechanisms by which Bcl-2 regulates apoptosis could provide insights for a rational design of approaches to enhance the susceptibility to drug-induced cell death.

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.

References (54)

  • C.D. Scatena et al.

    Mitotic phosphorylation of Bcl-2 during normal cell cycle progression and taxol-induced growth arrest

    J Biol Chem

    (1998)
  • J.A. Houghton

    Apoptosis and drug response

    Curr Opin Oncol

    (1999)
  • J.C. Reed

    Mechanisms of apoptosis avoidance in cancer

    Curr Opin Oncol

    (1999)
  • G. Kroemer

    The proto-oncogene Bcl-2 and its role in regulating apoptosis

    Nature Med

    (1997)
  • J.C. Reed

    Double identity for proteins of the Bcl-2 family

    Nature

    (1997)
  • J.C. Reed

    Bcl-2prevention of apoptosis as a mechanism of drug resistance

    Hematol Oncol Clin North Am

    (1995)
  • D. Decaudin et al.

    Bcl-2 and Bcl-XL antagonize the mitochondrial dysfunction preceding nuclear apoptosis induced by chemotherapeutic agents

    Cancer Res

    (1997)
  • W.S. El-Deiry

    Role of oncogenes in resistance and killing by cancer therapeutic agents

    Curr Opin Oncol

    (1997)
  • B. Jansen et al.

    Bcl-2 antisense therapy chemosensitizes human melanoma in SCID mice

    Nature Med

    (1998)
  • G.S. Wu et al.

    Apoptotic death of tumor cells correlates with chemosensitivity, independent of p53 or Bcl-2

    Clin Cancer Res

    (1996)
  • J.G. Reeve et al.

    Expression of apoptosis-regulatory genes in lung tumour cell linesrelationship to p53 expression and relevance to acquired drug resistance

    Br J Cancer

    (1996)
  • P.J. Beale et al.

    BCL-2 family protein expression and platinum drug resistance in ovarian carcinoma

    Br J Cancer

    (2000)
  • A.G. Eliopoulos et al.

    The control of apoptosis and drug resistance in ovarian cancerinfluence of p53 and Bcl-2

    Oncogene

    (1995)
  • D.X. Yin et al.

    BCL-2 expression delays drug-induced apoptosis but does not increase clonogenic survival after drug treatment in HeLa cells

    Cancer Res

    (1995)
  • G.P. Amarante-Mendes et al.

    Anti-apoptotic oncogenes prevent caspase-dependent and independent commitment for cell death

    Cell Death Diff

    (1998)
  • D. Del Bufalo et al.

    Lonidamine induces apoptosis in drug-resistant cells independently of the p53 gene

    J Clin Invest

    (1996)
  • A. Biroccio et al.

    Bcl-2 inhibits mitochondrial metabolism and lonidamine-induced apoptosis in adriamycin-resistant MCF7 cells

    Int J Cancer

    (1999)
  • Cited by (38)

    • CIL-102 interacts with microtubule polymerization and causes mitotic arrest following apoptosis in the human prostate cancer PC-3 cell line

      2005, Journal of Biological Chemistry
      Citation Excerpt :

      Despite the controversy regarding the role of Bcl-2 phosphorylation in anti-microtubule drug-induced apoptosis, several studies have demonstrated that Bcl-2 phosphorylation can be specifically induced by drugs that affect microtubule depolymerization or prevent microtubule assembly. This effect is not seen with DNA-damaging agents (29). Additionally, disruption of microtubule structures and induction of apoptosis by anti-microtubule drugs have been associated with altering a variety of cellular signaling pathways, such as Ras/Raf, protein kinase C/protein kinase A, mitogen-activated protein kinases/c-Jun N-terminal kinase, and p34cdc2.

    View all citing articles on Scopus
    View full text