Carnosic Acid Modulates Akt/IKK/NF-jB Signaling by PP2A and Induces Intrinsic and Extrinsic Pathway Mediated Apoptosis in Human Prostate Carcinoma PC-3 Cells
IR@IICB: CSIR-Indian Institute of Chemical Biology, Kolkata
View Archive Info| Field | Value | |
| Title |
Carnosic Acid Modulates Akt/IKK/NF-jB Signaling by PP2A
and Induces Intrinsic and Extrinsic Pathway Mediated Apoptosis
in Human Prostate Carcinoma PC-3 Cells
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| Creator |
Kar, Susanta
Palit, Shreyasi Basu Ball , Writoban Das, Pijush K |
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| Subject |
Infectious Diseases and Immunology
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| Description |
This study investigates the efficacy of carnosic
acid (CA), a polyphenolic diterpene, isolated from the plant
rosemary (Rosemarinus officinalis), on androgen-independent
human prostate cancer PC-3 cells. CA induced antiproliferative
effects in PC-3 cells in a concentration- and
time-dependent manner, which was due to apoptotic
induction as evident from flow-cytometry, DNA laddering
and TUNEL assay. Apoptosis was associated with the
activation of caspase-8, -9, -3 and -7, increase in Bax:Bcl-2
ratio, release of cytochrome-c and decrease in expression
of inhibitor of apoptosis (IAP) family of proteins. Apoptosis
was attenuated upon pretreatment with specific
inhibitors of caspase-8 (Z-IETD-fmk) and caspase-9 (ZLEHD-
fmk) suggesting the involvement of both intrinsic
and extrinsic apoptotic cascades. Further, apoptosis resulted
from the inhibition of IKK/NF-jB pathway as evident
from decreased DNA binding activity, nuclear translocation
of p50 and p65 and IjBa phosphorylation. The downregulation
of IKK/NF-jB was associated with inhibition of
Akt phosphorylation and its kinase activity with a concomitant
increase in the serine/threonine protein phosphatase
2A (PP2A) activity. Pharmacologic inhibition of PP2A
by okadaic acid and calyculin A, significantly reversed
CA-mediated apoptotic events in PC-3 cells indicating that
CA induced apoptosis by activation of PP2A through
modulation of Akt/IKK/NF-jB pathway. In addition, CA
induced apoptosis in another androgen refractory prostat cancer DU145 cells via intrinsic pathway as evidenced
from the activation of caspase 3, cleavage of PARP,
increase in Bax:Bcl-2 ratio and cytochrome-c release.
Carnosic acid, therefore, may have the potential for use in
the prevention and/or treatment of prostate cancer.
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| Publisher |
Kluwer
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| Date |
2012
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| Type |
Article
PeerReviewed |
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| Format |
application/pdf
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| Identifier |
http://www.eprints.iicb.res.in/1482/1/APOPTOSIS_17(_7)735%2D747;2012[2].pdf
Kar, Susanta and Palit, Shreyasi and Basu Ball , Writoban and Das, Pijush K (2012) Carnosic Acid Modulates Akt/IKK/NF-jB Signaling by PP2A and Induces Intrinsic and Extrinsic Pathway Mediated Apoptosis in Human Prostate Carcinoma PC-3 Cells. Apoptosis, 17 (7). pp. 735-747. |
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| Relation |
http://dx.doi.org/10.1007/s10495-012-0715-4
http://www.eprints.iicb.res.in/1482/ |
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