Invited
Speaker
Regulation of mitochondrial metabolism: Yet another facet
in the intriguing biology of the onco-protein Bcl-2
Shazib Pervaiz
Singapore
The anti-apoptotic members of the Bcl-2 family, such as Bcl-2, are
overexpressed in a variety of cancers and provide cancer cells with
a survival advantage by maintaining mitochondrial integrity and preventing
bioenergetic crisis. Our recent work has highlighted a novel mechanism
of action of Bcl-2 in that the apoptosis inhibitory activity of Bcl-2
was linked to its ability to function as a pro-oxidant, contrary to
its reported anti-oxidant activity. Overexpression of Bcl-2 resulted
in a slight increase in intracellular superoxide production, which
inhibited death signaling and promoted cell survival1.
More recently, we have linked this ability of Bcl-2 to an increase
in mitochondrial oxygen consumption and cytochrome C oxidase activity
in tumor cells2. Furthermore, we provide evidence to link
Bcl-2 expression to increased targeting of the complex IV sub units
to the mitochondria as a probable mechanism of the mitochondrial regulatory
activity of Bcl-23. We propose a model whereby over expression
of Bcl-2 promotes cell survival not only by way of blocking mitochondrial
permeabilization and egress of death amplifying factors, but also
by maintaining cellular/mitochondrial metabolism and permissive levels
of intracellular ROS that do not overwhelm the cellular anti-oxidant
defense systems. These insights into the novel biology of this remarkable
protein could have potential implications for the management of cancers
where Bcl-2 overexpression poses a major therapeutic challenge.
1. Clement, M. V., Hirpara, J. L., and Pervaiz,
S. (2003) Cell Death Differ 10,
1273-85
2. Chen, Z. X., and Pervaiz, S. (2007) Cell Death
Differ 14, 1617-27
3. Chen, Z. X.,and Pervaiz, S. (2009) Cell Death
Diff. (In Press)
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