Adiponectin-activated AMPK stimulates dephosphorylation of AKT through protein phosphatase 2A activation.
Low serum levels of adiponectin are a high risk factor for various types of cancer. Although adiponectin inhibits proliferation and metastasis of breast cancer cells, the underlying molecular mechanisms remain obscure. In this study, we show that adiponectin-activated AMPK reduces the invasiveness of MDA-MB-231 cells by stimulating dephosphorylation of AKT by increasing protein phosphatase 2A (PP2A) activity. Among the various regulatory B56 subunits, B56gamma was directly phosphorylated by AMPK at Ser(298) and Ser(336), leading to an increase of PP2A activity through dephosphorylation of PP2Ac at Tyr(307). We also show that both the blood levels of adiponectin and the tissue levels of PP2A activity were decreased in breast cancer patients and that the direct administration of adiponectin into tumor tissues stimulates PP2A activity. Taken together, these findings show that adiponectin, derived from adipocytes, negatively regulates the invasiveness of breast cancer cells by activating the tumor suppressor PP2A.
Department of Life Science, Research Center for Women's Diseases, Sookmyung Women's University, Seoul, Korea.
Kun-yong
KY
Kim
Ahmi
A
Baek
Ji-Eun
JE
Hwang
Yeon A
YA
Choi
Joon
J
Jeong
Myeong-Sok
MS
Lee
Dea Ho
DH
Cho
Jong-Seok
JS
Lim
Keun Il
KI
Kim
Young
Y
Yang
D000091162:AMP-Activated Protein Kinase Kinases; D052242:Adiponectin / Q000494:pharmacology*; D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects / Q000201:enzymology; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D006801:Humans; D007527:Isoenzymes; D051379:Mice; D008807:Mice, Inbred BALB C; D009362:Neoplasm Metastasis; D010766:Phosphorylation / Q000187:drug effects; D011494:Protein Kinases / Q000378:metabolism*; D054648:Protein Phosphatase 2 / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*
D052242:Adiponectin; D007527:Isoenzymes; D011494:Protein Kinases; D051057:Proto-Oncogene Proteins c-akt; D000091162:AMP-Activated Protein Kinase Kinases; D054648:Protein Phosphatase 2