Resveratrol mediated cell death in cigarette smoke transformed breast epithelial cells is through induction of p21Waf1/Cip1 and inhibition of long patch base excision repair pathway
(2014) In Toxicology and Applied Pharmacology 275(3). p.31-221- Abstract
Cigarette smoking is a key factor for the development and progression of different cancers including mammary tumor in women. Resveratrol (Res) is a promising natural chemotherapeutic agent that regulates many cellular targets including p21, a cip/kip family of cyclin kinase inhibitors involved in DNA damage-induced cell cycle arrest and blocking of DNA replication and repair. We have recently shown that cigarette smoke condensate (CSC) prepared from commercially available Indian cigarette can cause neoplastic transformation of normal breast epithelial MCF-10A cell. Here we studied the mechanism of Res mediated apoptosis in CSC transformed (MCF-10A-Tr) cells in vitro and in vivo. Res mediated apoptosis in MCF-10A-Tr cells was a p21... (More)
Cigarette smoking is a key factor for the development and progression of different cancers including mammary tumor in women. Resveratrol (Res) is a promising natural chemotherapeutic agent that regulates many cellular targets including p21, a cip/kip family of cyclin kinase inhibitors involved in DNA damage-induced cell cycle arrest and blocking of DNA replication and repair. We have recently shown that cigarette smoke condensate (CSC) prepared from commercially available Indian cigarette can cause neoplastic transformation of normal breast epithelial MCF-10A cell. Here we studied the mechanism of Res mediated apoptosis in CSC transformed (MCF-10A-Tr) cells in vitro and in vivo. Res mediated apoptosis in MCF-10A-Tr cells was a p21 dependent event. It increased the p21 protein expression in MCF-10A-Tr cells and MCF-10A-Tr cells-mediated tumors in xenograft mice. Res treatment reduced the tumor size(s) and expression of anti-apoptotic proteins (e.g. PI3K, AKT, NFκB) in solid tumor. The expressions of cell cycle regulatory (Cyclins, CDC-2, CDC-6, etc.), BER associated (Pol-β, Pol-δ, Pol-ε, Pol-η, RPA, Fen-1, DNA-Ligase-I, etc.) proteins and LP-BER activity decreased in MCF-10A-Tr cells but remain significantly unaltered in isogenic p21 null MCF-10A-Tr cells after Res treatment. Interestingly, no significant changes were noted in SP-BER activity in both the cell lines after Res exposure. Finally, it was observed that increased p21 blocks the LP-BER in MCF-10A-Tr cells by increasing its interaction with PCNA via competing with Fen-1 after Res treatment. Thus, Res caused apoptosis in CSC-induced cancer cells by reduction of LP-BER activity and this phenomenon largely depends on p21.
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- author
- Mohapatra, Purusottam LU ; Satapathy, Shakti Ranjan LU ; Das, Dipon ; Siddharth, Sumit ; Choudhuri, Tathagata and Kundu, Chanakya Nath
- publishing date
- 2014-03-15
- type
- Contribution to journal
- publication status
- published
- keywords
- Animals, Antineoplastic Agents/pharmacology, Apoptosis/drug effects, Breast Neoplasms/drug therapy, Cell Cycle/drug effects, Cell Death/drug effects, Cell Line, Transformed, Cell Transformation, Neoplastic/drug effects, Cyclin-Dependent Kinase Inhibitor p21/genetics, DNA Damage/drug effects, DNA Repair/drug effects, Dose-Response Relationship, Drug, Epithelial Cells/drug effects, Female, Flap Endonucleases/metabolism, Humans, Mammary Glands, Human/drug effects, Mice, Mice, Inbred BALB C, Proliferating Cell Nuclear Antigen/metabolism, RNA Interference, Resveratrol, Signal Transduction/drug effects, Smoke/adverse effects, Smoking/adverse effects, Stilbenes/pharmacology, Time Factors, Transfection, Up-Regulation, Xenograft Model Antitumor Assays
- in
- Toxicology and Applied Pharmacology
- volume
- 275
- issue
- 3
- pages
- 31 - 221
- publisher
- Academic Press
- external identifiers
-
- pmid:24467951
- scopus:84896695117
- ISSN
- 1096-0333
- DOI
- 10.1016/j.taap.2014.01.011
- language
- English
- LU publication?
- no
- additional info
- Copyright © 2014 Elsevier Inc. All rights reserved.
- id
- d0f0de36-0add-4a01-9a64-aac6b8309149
- date added to LUP
- 2025-01-30 10:32:45
- date last changed
- 2025-01-31 04:08:08
@article{d0f0de36-0add-4a01-9a64-aac6b8309149,
abstract = {{<p>Cigarette smoking is a key factor for the development and progression of different cancers including mammary tumor in women. Resveratrol (Res) is a promising natural chemotherapeutic agent that regulates many cellular targets including p21, a cip/kip family of cyclin kinase inhibitors involved in DNA damage-induced cell cycle arrest and blocking of DNA replication and repair. We have recently shown that cigarette smoke condensate (CSC) prepared from commercially available Indian cigarette can cause neoplastic transformation of normal breast epithelial MCF-10A cell. Here we studied the mechanism of Res mediated apoptosis in CSC transformed (MCF-10A-Tr) cells in vitro and in vivo. Res mediated apoptosis in MCF-10A-Tr cells was a p21 dependent event. It increased the p21 protein expression in MCF-10A-Tr cells and MCF-10A-Tr cells-mediated tumors in xenograft mice. Res treatment reduced the tumor size(s) and expression of anti-apoptotic proteins (e.g. PI3K, AKT, NFκB) in solid tumor. The expressions of cell cycle regulatory (Cyclins, CDC-2, CDC-6, etc.), BER associated (Pol-β, Pol-δ, Pol-ε, Pol-η, RPA, Fen-1, DNA-Ligase-I, etc.) proteins and LP-BER activity decreased in MCF-10A-Tr cells but remain significantly unaltered in isogenic p21 null MCF-10A-Tr cells after Res treatment. Interestingly, no significant changes were noted in SP-BER activity in both the cell lines after Res exposure. Finally, it was observed that increased p21 blocks the LP-BER in MCF-10A-Tr cells by increasing its interaction with PCNA via competing with Fen-1 after Res treatment. Thus, Res caused apoptosis in CSC-induced cancer cells by reduction of LP-BER activity and this phenomenon largely depends on p21.</p>}},
author = {{Mohapatra, Purusottam and Satapathy, Shakti Ranjan and Das, Dipon and Siddharth, Sumit and Choudhuri, Tathagata and Kundu, Chanakya Nath}},
issn = {{1096-0333}},
keywords = {{Animals; Antineoplastic Agents/pharmacology; Apoptosis/drug effects; Breast Neoplasms/drug therapy; Cell Cycle/drug effects; Cell Death/drug effects; Cell Line, Transformed; Cell Transformation, Neoplastic/drug effects; Cyclin-Dependent Kinase Inhibitor p21/genetics; DNA Damage/drug effects; DNA Repair/drug effects; Dose-Response Relationship, Drug; Epithelial Cells/drug effects; Female; Flap Endonucleases/metabolism; Humans; Mammary Glands, Human/drug effects; Mice; Mice, Inbred BALB C; Proliferating Cell Nuclear Antigen/metabolism; RNA Interference; Resveratrol; Signal Transduction/drug effects; Smoke/adverse effects; Smoking/adverse effects; Stilbenes/pharmacology; Time Factors; Transfection; Up-Regulation; Xenograft Model Antitumor Assays}},
language = {{eng}},
month = {{03}},
number = {{3}},
pages = {{31--221}},
publisher = {{Academic Press}},
series = {{Toxicology and Applied Pharmacology}},
title = {{Resveratrol mediated cell death in cigarette smoke transformed breast epithelial cells is through induction of p21Waf1/Cip1 and inhibition of long patch base excision repair pathway}},
url = {{http://dx.doi.org/10.1016/j.taap.2014.01.011}},
doi = {{10.1016/j.taap.2014.01.011}},
volume = {{275}},
year = {{2014}},
}