NDLI: Quercetin enhances hypoxia-mediated apoptosis via direct inhibition of AMPK activity in HCT116 colon cancer

Content Provider	Springer Nature Link
Author	Kim, Hak Su Wannatung, Tirawat Lee, Sooho Yang, Woo Kyeom Chung, Sung Hyun Lim, Jong Seok Choe, Wonchae Kang, Insug Kim, Sung Soo Ha, Joohun
Copyright Year	2012
Abstract	Tumor hypoxia is considered the best validated target in clinical oncology because of its significant contribution to chemotherapy failure and drug resistance. As an approach to target hypoxia, we assessed the potential of quercetin, a flavonoid widely distributed in plants, as a anticancer agent under hypoxic conditions and examined its pharmacological mechanisms by primarily focusing on the role of AMP-activated protein kinase (AMPK). Quercetin significantly attenuated tumor growth in an HCT116 cancer xenograft in vivo model with a substantial reduction of AMPK activity. In a cell culture system, quercetin more dramatically induced apoptosis of HCT116 cancer cells under hypoxic conditions than normoxic conditions, and this was tightly associated with inhibition of hypoxia-induced AMPK activity. An in vitro kinase assay demonstrated that quercetin directly inhibits AMPK activity. Inhibition of AMPK by expressing a dominant-negative form resulted in an increase of apoptosis under hypoxia, and a constitutively active form of AMPK effectively blocked quercetin-induced apoptosis under hypoxia. Collectively, our data suggest that quercetin directly inhibits hypoxia-induced AMPK, which plays a protective role against hypoxia. Quercetin also reduced the activity of hypoxia-inducible factor-1 (HIF-1), a major transcription factor for adaptive cellular response to hypoxia. Moreover, quercetin sensitized HCT116 cancer cells to the anticancer drugs cisplatin and etoposide under hypoxic conditions. Our findings suggest that AMPK may serve as a novel target for overcoming tumor hypoxia-associated negative aspects.
Starting Page	938
Ending Page	949
Page Count	12
File Format	PDF
ISSN	13608185
Journal	Apoptosis
Volume Number	17
Issue Number	9
e-ISSN	1573675X
Language	English
Publisher	Springer US
Publisher Date	2012-06-10
Publisher Place	Boston
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	Quercetin AMPK Hypoxia HIF-1α Apotosis Virology Biochemistry Oncology Cancer Research Cell Biology
Content Type	Text
Resource Type	Article
Subject	Pharmaceutical Science Biochemistry (medical) Cell Biology Clinical Biochemistry Cancer Research Pharmacology

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