Embelin inhibits growth and induces apoptosis through the suppression of Akt/mTOR/S6K1 signaling cascades.

Abstract

BACKGROUND:

Akt/mTOR/S6K1 signaling cascades play an important role both in the survival and proliferation of tumor cells.

METHODS:

In the present study, we investigated the effects of embelin (EB), identified primarily from the Embelia ribes plant, on the Akt/mTOR/S6K1 activation, associated gene products, cellular proliferation, and apoptosis in human prostate cancer cells.

RESULTS:

EB exerted significant cytotoxic and suppressive effects on Akt and mTOR activation against androgen-independent PC-3 cells as compared to androgen-dependent LNCaP cells. Moreover, EB suppressed the constitutive activation of Akt/mTOR/S6K1 signaling cascade, which correlated with the induction of apoptosis as characterized by accumulation of cells in subG1 phase, positive Annexin V binding, down-regulation of anti-apoptotic (Bcl-2, Bcl-xL, survivin, IAP-1, and IAP-2) and proliferative (cyclin D1) proteins, activation of caspase-3, and cleavage of PARP. We also observed that EB can significantly enhance the apoptotic effects of a specific pharmacological Akt inhibitor when used in combination and also caused broad inhibition of all the three kinases in Akt/mTOR/S6K1 signaling axis in PC-3 cells.

CONCLUSIONS:

EB inhibits multiple signaling cascades involved in tumorigenesis and can be used as a potential therapeutic candidate for both the prevention and treatment of prostate cancer.

• Authors: Seong Won Kim, Sung-Moo Kim, Hang Bae, Dongwoo Nam, Jun-Hee Lee, Seok-Geun Lee, Bum Sang Shim, Sung-Hoon Kim, Kyoo Seok Ahn, Seung-Hoon Choi, Gautam Sethi, Kwang Seok Ahn
• Journal: The Prostate (Prostate) Vol. 73 Issue 3 Pg. 296-305 (Feb 15 2013) ISSN: 1097-0045 [Electronic] United States
• PMID: 22887478 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Wiley Periodicals, Inc.

Chemical References

• Androgens
• Benzoquinones
• Cyclin D1
• Proto-Oncogene Proteins c-akt
• Ribosomal Protein S6 Kinases, 70-kDa
• TOR Serine-Threonine Kinases
• ribosomal protein S6 kinase, 70kD, polypeptide 1
• embelin

Topics

• Androgens (metabolism)
• Apoptosis (drug effects)
• Benzoquinones (pharmacology)
• Cell Cycle (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Cyclin D1 (metabolism)
• Dose-Response Relationship, Drug
• Down-Regulation (drug effects)
• Humans
• In Vitro Techniques
• Male
• Prostatic Neoplasms (metabolism, pathology)
• Proto-Oncogene Proteins c-akt (antagonists & inhibitors, metabolism)
• Ribosomal Protein S6 Kinases, 70-kDa (antagonists & inhibitors, metabolism)
• Signal Transduction (drug effects)
• TOR Serine-Threonine Kinases (antagonists & inhibitors, metabolism)
• Time Factors