Identification of an annonaceous acetogenin mimetic, AA005, as an AMPK activator and autophagy inducer in colon cancer cells.
Annonaceous acetogenins, a large family of naturally occurring polyketides isolated from various species of the plant genus Annonaceae, have been found to exhibit significant cytotoxicity against a variety of cancer cells. Previous studies showed that these compounds could act on the mitochondria complex-I and block the corresponding electron transport chain and terminate ATP production. However, more details of the mechanisms of action remain ambiguous. In this study we tested the effects of a set of mimetics of annonaceous acetogenin on some cancer cell lines, and report that among them AA005 exhibits the most potent antitumor activity. AA005 depletes ATP, activates AMP-activated protein kinase (AMPK) and inhibits mTOR complex 1 (mTORC1) signal pathway, leading to growth inhibition and autophagy of colon cancer cells. AMPK inhibitors compound C and inosine repress, while AMPK activator AICAR enhances, AA005-caused proliferation suppression and subsequent autophagy of colon cancer cells. AA005 enhances the ATP depletion and AMPK activation caused by 2-deoxyglucose, an inhibitor of mitochondrial respiration and glycolysis. AA005 also inhibits chemotherapeutic agent cisplatin-triggered up-regulation of mTOR and synergizes with this drug in suppression of proliferation and induction of apoptosis of colon cancer cells. These data indicate that AA005 is a new metabolic inhibitor which exhibits therapeutic potentials in colon cancer.
Division of Molecular Carcinogenesis and Targeted Therapy for Cancer, State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
Yong-Qiang
YQ
Liu
Xin
X
Cheng
Liang-Xia
LX
Guo
Chan
C
Mao
Yi-Jie
YJ
Chen
Hai-Xia
HX
Liu
Qi-Cai
QC
Xiao
Sheng
S
Jiang
Zhu-Jun
ZJ
Yao
Guang-Biao
GB
Zhou
D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D054378:Acetogenins / Q000737:chemistry*; D000255:Adenosine Triphosphate / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects*; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005233:Fatty Alcohols / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007783:Lactones / Q000737:chemistry / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology
C483824:AA005; D054378:Acetogenins; D005233:Fatty Alcohols; D007783:Lactones; D011720:Pyrazoles; D011743:Pyrimidines; C516138:dorsomorphin; D000255:Adenosine Triphosphate; D055372:AMP-Activated Protein Kinases