Arsenic induced apoptosis in malignant melanoma cells is enhanced by menadione through ROS generation, p38 signaling and p53 activation
IR@IICB: CSIR-Indian Institute of Chemical Biology, Kolkata
View Archive Info| Field | Value | |
| Title |
Arsenic induced apoptosis in malignant melanoma cells
is enhanced by menadione through ROS generation,
p38 signaling and p53 activation
|
|
| Creator |
Chowdhury, Rajdeep
Chowdhury, Suchandra Roychoudhury, Paromita Mandal, Chitra Chaudhuri, Keya |
|
| Subject |
Infectious Diseases and Immunology
Molecular & Human Genetics |
|
| Description |
Introduction Resistance to apoptosis is a prominent feature
of melanoma. Pharmacological concentration of
arsenic in combination with a widely known oxidant,
menadione was explored in this study to synergistically
sensitize malignant melanoma cells to apoptosis. The
molecular mechanism of apoptosis and the signalingpathways
involved were thoroughly investigated.
Materials methods and results Menadione synergized
NaAsO2 to significantly increase ROS generation and
facilitate the major apoptotic signaling events: alteration of
mitochondrial membrane potential, cytochrome c release
and anti-apoptotic protein Bcl-2 down-regulation and
subsequent activation of caspase-9 and caspase-3 followed
by poly-ADP-ribose polymerase-1 cleavage. Antioxidant
N-acetyl-L-cysteine antagonized these events. Investigation
of the signaling-pathway revealed significant suppression
of AP-1 activity but not NF-jB upon NaAsO2 and menadione
application. An increase in p38 phosphorylation and
p53 protein expression did also dictate the apoptotic
response. Suppression of p38 activation with SB203580
and inhibition of p53 expression by siRNA attenuated
apoptosis. Transfection of p53, in p53 null HCT cells
augmented the apoptotic events. Moreover, the treatment
also led to tumor size reduction in BALB/c mice developed
by intra-dermal B16 mouse melanoma cell injection;however, it had no detectable pro-proliferative or proapoptotic
effect on non-tumor keratinocytes, normal
fibroblasts or PBMC.
Conclusion This study thus provides an insight into
innovative mechanisms of melanoma sensitization, a
proper cure against which is still elusive. Taken together,
our data also provides the first evidence of arsenic activity
accentuation by menadione through modulation of specific
signaling-pathways.
|
|
| Date |
2009
|
|
| Type |
Article
PeerReviewed |
|
| Format |
application/pdf
|
|
| Identifier |
http://www.eprints.iicb.res.in/131/1/APOPTOSIS%2C14(1)%2C108%2D123%2C2009[134].pdf
Chowdhury, Rajdeep and Chowdhury, Suchandra and Roychoudhury, Paromita and Mandal, Chitra and Chaudhuri, Keya (2009) Arsenic induced apoptosis in malignant melanoma cells is enhanced by menadione through ROS generation, p38 signaling and p53 activation. Apoptosis, 14. pp. 108-123. |
|
| Relation |
http://dx.doi.org/10.1007/s10495-008-0284-8
http://www.eprints.iicb.res.in/131/ |
|