Role of the retinoblastoma (pRb)-E2F/DP pathway in cancer chemopreventive effects of green tea polyphenol epigallocatechin-3-gallate.
Because of the demonstrated role of green tea polyphenol epigallocatechin-3-gallate (EGCG) in cancer chemoprevention, there is considerable emphasis in understanding its mechanism of action. In this study, we assessed the involvement of the retinoblastoma (pRb)-E2F/DP pathway as an important contributor in the antiproliferative effects of EGCG. As shown by immunoblot analysis, EGCG treatment of A431 cells resulted in a dose- as well as time-dependent decrease in the total pRb with a relative increase in the hypophosphorylated form of pRb. EGCG also resulted in serine-780 phosphorylation of pRb in these cells. Further, EGCG was found to downregulate the protein expression of other members of the pRb family, viz. p130 and p107, in a dose- as well as time-dependent manner. This response was accompanied by downregulation in the protein expression of the E2F (1 through 5) family of transcription factors and their heterodimeric partners DP1 and DP2. Taken together, our study suggests that EGCG causes a downregulation of hyperphosphorylated pRb protein with a relative increase in hypophosphorylated pRb that, in turn, compromises with the availability of "free" E2F. This series of events leads to stoppage of cell cycle progression at the G1-->S phase transition thereby causing G0/G1 arrest and subsequent apoptotic cell death. This, to our knowledge, is the first study showing the involvement of the pRb-E2F/DP pathway in antiproliferative and apoptotic effects of EGCG.
Ahmad
Nihal
N
Department of Dermatology, Case Western Reserve University, The Research Institute of University Hospitals of Cleveland, 11100 Euclid Avenue, Cleveland, Ohio 44106, USA.
Adhami
Vaqar M
VM
Gupta
Sanjay
S
Cheng
Pingyan
P
Mukhtar
Hasan
H
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D002392:Catechin / Q000031:analogs & derivatives / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects*; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D006801:Humans; D010766:Phosphorylation / Q000187:drug effects; D012175:Retinoblastoma; D016160:Retinoblastoma Protein / Q000378:metabolism*; D013662:Tea / Q000737:chemistry*; D014157:Transcription Factors / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D016160:Retinoblastoma Protein; D013662:Tea; D014157:Transcription Factors; D002392:Catechin; C045651:epigallocatechin gallate