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Activation of AMP Kinase by Zyflamend, a Well‐Defined Blend of Herbal Extracts
Author(s) -
MacDonald Amber Frances,
Han Anna Frances,
Donohoe Dallas,
Whelan Jay
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.691.26
Subject(s) - ampk , protein kinase a , kinase , amp activated protein kinase , chemistry , biology , microbiology and biotechnology , cancer research , biochemistry
Zyflamend, a select blend of 10 herbal extracts, has been shown to inhibit prostate cancer (PCa) in vitro and in vivo at human equivalent doses. Zyflamend's tumor suppressive effects are partly due to the phosphorylation and activation of 5′ adenosine monophosphate‐activated protein kinase (AMPK), a master energy sensor of the cell that restores homeostasis in response to metabolic stress. AMPK activation by Zyflamend inhibits lipogenesis and enhances mitochondrial fatty acid oxidation, depriving proliferating tumor cells of necessary fatty acids for the generation of new membranes (Zhao et al, 2015). However, the mechanism of action whereby Zyflamend phosphorylates AMPK (pAMPK) is unknown. Currently, the literature has identified four kinases that phosphorylate the catalytic subunit of AMPK at Thr172, thereby increasing activity. Two of these kinases that most likely activate AMPK in PCa are liver kinase B1 (LKB1) and calcium/calmodulin‐dependent protein kinase kinase β (CaMKKβ). First, inactivation of LKB1 is associated with a variety of cancers, including reduced expression in PCa tissue. In addition, knockdown of LKB1 promotes the proliferation of PCa. Second, CaMKKβ has been negatively associated with castrate‐resistant PCa, where decreased expression increases proliferation and over expression reduces tumor growth in vivo . Therefore, the objective of this study was to determine the upstream kinase of AMPK activation by Zyflamend in castrate‐resistant PCa cells. CWR22Rv1, a castrate‐resistant PCa cell line, expresses LKB1 and CaMKKβ. When cells were treated with chemical inhibitors of LKB1 (radicicol) or CaMKKβ (STO‐609), pAMPK was reduced. Treatment with Zyflamend in the presence of radicicol failed to completely restore pAMPK at Thr172, while pAMPK was restored to the Zyflamend‐stimulated levels in the presence of STO‐609. These data suggest that Zyflamend‐stimulated pAMPK is partially dependent upon LKB1, but independent of CaMKKβ activity. Support or Funding Information Supported by the Tennessee Agricultural Experiment Station Hatch grant #TEN00441