Green tea polyphenol EGCG sensitizes human prostate carcinoma LNCaP cells to TRAIL-mediated apoptosis and synergistically inhibits biomarkers associated with angiogenesis and metastasis

I. A. Siddiqui, A. Malik, V. M. Adhami, M. Asim, B. B. Hafeez, S. Sarfaraz, H. Mukhtar

Research output: Contribution to journalArticle

162 Citations (Scopus)

Abstract

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL/Apo2L) is a promising candidate for cancer therapy, however, emergence of drug resistance limits its potential use. Here, we report for the first time that epigallocatechin-3-gallate (EGCG), the major polyphenolic constituent of green tea, sensitizes TRAIL-resistant LNCaP cells to TRAIL-mediated apoptosis through modulation of intrinsic and extrinsic apoptotic pathways. When combined with EGCG, Apo2L/TRAIL exhibited enhanced apoptotic activity in LNCaP cells characterized by three major molecular events. First, apoptosis induction was accompanied by the upregulation of poly(ADP-ribose) polymerase cleavage and modulation of pro- and antiapoptotic Bcl2 family of proteins. A synergistic inhibition of inhibitors of apoptosis with concomitant increase in caspase cleavage was observed. Second, pretreatment of cells with EGCG resulted in modulation of death-inducing signaling cascade complex involving DR4/TRAIL R1, Fas-associated death domain and FLICE-inhibitory protein proteins. Last, we observed a synergistic inhibition in the invasion and migration of LNCaP cells. This effect was observed to be mediated through inhibition in the protein expression of vascular endothelial growth factor, uPA and angiopoietin 1 and 2. Further, the activity and protein expression of MMP-2, -3 and -9 and upregulation of TIMP1 in cells treated with a combination of EGCG and TRAIL was observed. These data might have implications for developing new strategies aimed at eliminating prostate cancer cells resistant to TRAIL.

Original languageEnglish (US)
Pages (from-to)2055-2063
Number of pages9
JournalOncogene
Volume27
Issue number14
DOIs
StatePublished - Mar 27 2008

Fingerprint

Polyphenols
Tea
Prostate
Biomarkers
Apoptosis
Neoplasm Metastasis
Carcinoma
Proteins
Up-Regulation
Death Domain Receptor Signaling Adaptor Proteins
CASP8 and FADD-Like Apoptosis Regulating Protein
Angiopoietin-2
Angiopoietin-1
Poly(ADP-ribose) Polymerases
Caspases
Matrix Metalloproteinases
Drug Resistance
Vascular Endothelial Growth Factor A
Cell Movement
Prostatic Neoplasms

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

Green tea polyphenol EGCG sensitizes human prostate carcinoma LNCaP cells to TRAIL-mediated apoptosis and synergistically inhibits biomarkers associated with angiogenesis and metastasis. / Siddiqui, I. A.; Malik, A.; Adhami, V. M.; Asim, M.; Hafeez, B. B.; Sarfaraz, S.; Mukhtar, H.

In: Oncogene, Vol. 27, No. 14, 27.03.2008, p. 2055-2063.

Research output: Contribution to journalArticle

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abstract = "Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL/Apo2L) is a promising candidate for cancer therapy, however, emergence of drug resistance limits its potential use. Here, we report for the first time that epigallocatechin-3-gallate (EGCG), the major polyphenolic constituent of green tea, sensitizes TRAIL-resistant LNCaP cells to TRAIL-mediated apoptosis through modulation of intrinsic and extrinsic apoptotic pathways. When combined with EGCG, Apo2L/TRAIL exhibited enhanced apoptotic activity in LNCaP cells characterized by three major molecular events. First, apoptosis induction was accompanied by the upregulation of poly(ADP-ribose) polymerase cleavage and modulation of pro- and antiapoptotic Bcl2 family of proteins. A synergistic inhibition of inhibitors of apoptosis with concomitant increase in caspase cleavage was observed. Second, pretreatment of cells with EGCG resulted in modulation of death-inducing signaling cascade complex involving DR4/TRAIL R1, Fas-associated death domain and FLICE-inhibitory protein proteins. Last, we observed a synergistic inhibition in the invasion and migration of LNCaP cells. This effect was observed to be mediated through inhibition in the protein expression of vascular endothelial growth factor, uPA and angiopoietin 1 and 2. Further, the activity and protein expression of MMP-2, -3 and -9 and upregulation of TIMP1 in cells treated with a combination of EGCG and TRAIL was observed. These data might have implications for developing new strategies aimed at eliminating prostate cancer cells resistant to TRAIL.",
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