Anticancer properties of pomolic acid-induced AMP-activated protein kinase activation in MCF7 human breast cancer cells.
AMP-activated protein kinase (AMPK) is a sensor of cellular energy status found in all eukaryotes. Recent studies indicate that AMPK activation strongly suppresses cell proliferation in tumor cells, which requires high rates of protein synthesis and de novo fatty acid synthesis for their rapid growth. Pomolic acid (PA) has been previously described as being active in inhibiting the growth of cancer cells. In this study, we investigated PA activated AMPK, and this activity was related to proliferation and apoptosis in MCF7 breast cancer cells. PA inhibited cell proliferation and induced sub-G(1) arrest, elevating the mRNA levels of the apoptotic genes p53 and p21. PA activated caspase-3, -9, and poly(ADP-ribose) polymerase, and this effect was inhibited by z-VAD-fmk. AMPK activation was increased by treating cells with PA, inactivated by treating cells with a compound C, and co-treatment consisting of PA and aminoimidazole carboxamide ribonucleotide (AICAR) synergistically activated AMPK. These anti-cancer potentials of PA were accompanied by effects on de novo fatty acid synthesis as shown by the decreased expression of fatty acid synthase, and decreased acetyl-CoA carboxylase activation and incorporation of [(3)H]acetyl-CoA into fatty acids. In addition, PA inhibited key enzymes involved in protein synthesis such as mammalian target of rapamycin (mTOR), 70 kDa ribosomal protein S6 kinase (p70S6K), and eukaryotic translation initiation factor 4E-binding protein 1 (4EBP1). These results suggest that PA exerts anti-cancer properties through the modulation of AMPK pathways and its value as an anti-cancer agent in breast cancer therapy.
Department of Surgery, Chungnam National University Hospital, Daejeon 301–721, Korea.
Seog Hyeon
SH
Youn
Jin Sun
JS
Lee
Myung Sun
MS
Lee
Eun Young
EY
Cha
Phuong Thien
PT
Thuong
Je Ryong
JR
Kim
Eil Sung
ES
Chang
D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000103:Acetyl-CoA Carboxylase / Q000378:metabolism; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D064429:Fatty Acid Synthases / Q000378:metabolism; D005227:Fatty Acids / Q000096:biosynthesis; D005260:Female; D016193:G1 Phase / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D016158:Genes, p53; D006801:Humans; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D008517:Phytotherapy; D010936:Plant Extracts / Q000494:pharmacology / Q000627:therapeutic use*; D011065:Poly(ADP-ribose) Polymerases / Q000187:drug effects; D014176:Protein Biosynthesis / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D012265:Ribonucleotides / Q000494:pharmacology
D000972:Antineoplastic Agents, Phytogenic; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D005227:Fatty Acids; D010936:Plant Extracts; D012333:RNA, Messenger; D012265:Ribonucleotides; D000620:Aminoimidazole Carboxamide; C115535:pomolic acid; D009828:Oleanolic Acid; D064429:Fatty Acid Synthases; D011065:Poly(ADP-ribose) Polymerases; D055372:AMP-Activated Protein Kinases; D053148:Caspase 3; D053453:Caspase 9; D000103:Acetyl-CoA Carboxylase; C031143:AICA ribonucleotide