LIFE01200604005 Shri Somnath Ghosh - Homi Bhabha National ...

CHAPTER 4
DISCUSSION
Although the exact means by which p53 activates apoptosis is unclear, evidence has shown that
p53 mediates apoptosis by way of transcription-independent and transcription-dependent
mechanisms [267, 268]. p53 is known to regulate the expression of several proteins involved in
the apoptotic pathway and also interacts with BAX, BCL-XL, and BCL-2 to exert a direct
apoptotic effect at the level of the mitochondria [111, 269, 270].
Increased phosphorylation of p53, upregulation of Bax and down-regulation of Bcl-2 in proton
beam irradiated A549 cells as compared to γ-irradiated cells (Fig.3.2.3 and Fig.3.2.4) indicate the
activation of apoptotic pathways.
The noteworthy finding of this study is the biphasic activation of the sensor proteins, ATM and
DNA-PK and no activation of ATR by proton irradiation and the significant activation of Chk2
even at the gene level only in the proton beam irradiated cells (Fig.3.2.2). Such biphasic response
after irradiation with proton or other heavy ions have been observed and may be characteristics
of particle irradiation [271]. Unlike gamma irradiation, the biphasic induction of ATM and
DNA-PK following proton beam irradiation could be responsible for the activation of apoptotic
machinery, however, further studies in this direction will reveal the importance of such biphasic
response.
The use of proton beam therapy has definite advantage over gamma therapy. The mechanism of
apoptosis will give the clinician a handle to manipulate therapy for enhanced cell killing.
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