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.
Kim
Kun-yong
KY
Department of Life Science, Research Center for Women's Diseases, Sookmyung Women's University, Seoul, Korea.
Baek
Ahmi
A
Hwang
Ji-Eun
JE
Choi
Yeon A
YA
Jeong
Joon
J
Lee
Myeong-Sok
MS
Cho
Dea Ho
DH
Lim
Jong-Seok
JS
Kim
Keun Il
KI
Yang
Young
Y
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