Pomegranate extract induces apoptosis in human prostate cancer cells by modulation of the IGF-IGFBP axis.
The IGF axis is critical for the regulation of apoptosis in many human cancer cell lines. Recently, potent anti-tumorigenic effects of pomegranate juice and extracts have been reported. Consequently, pomegranate has potential not only as a treatment but also as a preventative measure against certain types of cancer, including prostate. In this study, we investigated the relationship between pomegranate-induced apoptosis in human prostate cancer cells and the IGF/IGFBP system. Treatment of LAPC4 prostate cancer cells with 10microg/ml POMx, a highly potent pomegranate extract prepared from skin and arils minus seeds and standardized to ellagitannin content (37% punicalagins by HPLC), resulted in inhibition of cell proliferation and induction of apoptosis. Interestingly, co-treatment with POMx and IGFBP-3 revealed synergistic stimulation of apoptosis and additive inhibition of cell growth. Western blot analysis revealed that treatment with POMx or POMx/IGFBP-3 combination resulted in increased JNK phosphorylation, and decreased Akt and mTOR activation, consistent with a growth inhibitory, pro-apoptotic function. We also investigated the relationship between IGF-1 and pomegranate-induced apoptosis in 22RV1 prostate cancer cells. Co-treatment with 100ng/ml IGF-1 completely blocked apoptosis induction by POMx. In contrast, IGF-I failed to inhibit POMx-induced apoptosis in R(-) cells, suggesting the importance of IGF-IR. POMx-treatment decreased Igf1 mRNA expression in a dose-dependent manner indicating that its actions also involve tumor-specific suppression of IGF-1. These studies revealed novel interactions between the IGF system and pomegranate-induced apoptosis.
Division of Pediatric Endocrinology, Mattel Children's Hospital, David Geffen School of Medicine, University of California, Los Angeles, USA.
Satomi
S
Koyama
Laura J
LJ
Cobb
Hemal H
HH
Mehta
Navindra P
NP
Seeram
David
D
Heber
Allan J
AJ
Pantuck
Pinchas
P
Cohen
D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D047348:Hydrolyzable Tannins / Q000032:analysis / Q000494:pharmacology; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000187:drug effects; D048031:JNK Mitogen-Activated Protein Kinases / Q000187:drug effects; D029561:Lythraceae / Q000737:chemistry*; D008297:Male; D010936:Plant Extracts / Q000737:chemistry / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases
D000972:Antineoplastic Agents, Phytogenic; D047348:Hydrolyzable Tannins; D018972:Insulin-Like Growth Factor Binding Protein 3; D047908:Intracellular Signaling Peptides and Proteins; D010936:Plant Extracts; C013515:ellagitannin; D007334:Insulin-Like Growth Factor I; C546842:MTOR protein, human; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; D048031:JNK Mitogen-Activated Protein Kinases