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.
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.
Cancer Biology Division, KIIT School of Biotechnology, KIIT University, Campus-11, Patia, Bhubaneswar, Orissa 751024, India.
Purusottam
P
Mohapatra
Cancer Biology Division, KIIT School of Biotechnology, KIIT University, Campus-11, Patia, Bhubaneswar, Orissa 751024, India.
Shakti Ranjan
SR
Satapathy
Cancer Biology Division, KIIT School of Biotechnology, KIIT University, Campus-11, Patia, Bhubaneswar, Orissa 751024, India.
Dipon
D
Das
Cancer Biology Division, KIIT School of Biotechnology, KIIT University, Campus-11, Patia, Bhubaneswar, Orissa 751024, India.
Sumit
S
Siddharth
Institute of Life Sciences, Nalco Square, Bhubaneswar, Orissa 751023, India; Department of Biotechnology, Visva Bharati University, Santiniketan, West Bengal, India.
Tathagata
T
Choudhuri
Cancer Biology Division, KIIT School of Biotechnology, KIIT University, Campus-11, Patia, Bhubaneswar, Orissa 751024, India. Electronic address: cnkundu@gmail.com.
Chanakya Nath
CN
Kundu
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D002461:Cell Line, Transformed; D002471:Cell Transformation, Neoplastic / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism*; D004249:DNA Damage / Q000187:drug effects; D004260:DNA Repair / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005260:Female; D045585:Flap Endonucleases / Q000378:metabolism; D006801:Humans; D042361:Mammary Glands, Human / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D034622:RNA Interference; D000077185:Resveratrol; D015398:Signal Transduction / Q000187:drug effects; D012906:Smoke / Q000009:adverse effects*; D012907:Smoking / Q000009:adverse effects*; D013267:Stilbenes / Q000494:pharmacology*; D013997:Time Factors; D014162:Transfection; D015854:Up-Regulation; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018809:Proliferating Cell Nuclear Antigen; D012906:Smoke; D013267:Stilbenes; D045585:Flap Endonucleases; C468317:FEN1 protein, human; D000077185:Resveratrol
Breast cancer; Cigarette smoke condensate; DNA damage repair; Resveratrol; Transformation