Widdrol induces apoptosis via activation of AMP-activated protein kinase in colon cancer cells.

Abstract

Widdrol, a natural sesquiterpene present in Juniperus sp., has been shown to exert anticancer and antifungal effects. Emerging evidence has suggested that AMP-activated protein kinase (AMPK), which functions as a cellular energy sensor, is a potential therapeutic target for human cancers. In this study, we found that AMPK mediates the anticancer effects of widdrol through induction of apoptosis in HT-29 colon cancer cells. We showed that widdrol induced the phosphorylation of AMPK in a dose- and time-dependent manner. The selective AMPK inhibitor compound C abrogated the inhibitory effect of widdrol on HT-29 cell growth. In addition, we demonstrated that widdrol induced apoptosis and this was associated with the activation of caspases, including caspase‑3/7 and caspase-9, in HT-29 cells. We also demonstrated that transfection of HT-29 cells with AMPK siRNAs significantly suppressed the widdrol-mediated apoptosis and the activation of caspases. However, cell cycle arrest induced by widdrol was not affected by transfection of HT-29 cells with AMPK siRNAs. Furthermore, widdrol inhibited HT-29 tumor growth in a human tumor xenograft model. Taken together, our results suggest that the anticancer effect of widdrol may be mediated, at least in part, by induction of apoptosis via AMPK activation.

• Authors: Moo Rim Kang, Song-Kyu Park, Chang Woo Lee, Ig Jun Cho, Yeong Nang Jo, Jeong Wook Yang, Jin-Ah Kim, Jieun Yun, Ki Hoon Lee, Hyun Ju Kwon, Byung Woo Kim, Kiho Lee, Jong Soon Kang, Hwan Mook Kim
• Journal: Oncology reports (Oncol Rep) Vol. 27 Issue 5 Pg. 1407-12 (May 2012) ISSN: 1791-2431 [Electronic] Greece
• PMID: 22266984 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents, Phytogenic
• Benzocycloheptenes
• widdrol
• AMP-Activated Protein Kinases
• Caspases

Topics

• AMP-Activated Protein Kinases (metabolism)
• Animals
• Antineoplastic Agents, Phytogenic (administration & dosage, pharmacology)
• Apoptosis (drug effects)
• Benzocycloheptenes (administration & dosage, pharmacology)
• Caspases (metabolism)
• Cell Cycle Checkpoints (drug effects)
• Cell Line, Tumor
• Colonic Neoplasms (drug therapy, enzymology)
• Enzyme Activation (drug effects)
• Female
• Humans
• Mice
• Mice, Inbred BALB C
• Phosphorylation (drug effects)
• Signal Transduction (drug effects)
• Xenograft Model Antitumor Assays