Acrp30 inhibits leptin-induced metastasis by downregulating the JAK/STAT3             pathway via AMPK activation in aggressive SPEC-2 endometrial cancer cells.
Obesity is a well-established risk factor for endometrial cancer, due in             part to the adipokines generated by adipose tissue, such as adiponectin (also             known as Acrp30) and leptin, which are associated with many endocrine-related             cancers. Recent reports suggested that Acrp30 inhibits leptin-stimulated cell             proliferation in HEC-1A and RL95-2 endometrial cancer cell lines, and that the             serum leptin/Acrp30 ratio plays an important role in endometrial cancer development.             We explored whether Acrp30 could reverse the leptin-induced metastasis phenotype             in the SPEC-2 endometrial cancer cell line. Transcripts for Acrp30 receptors (AdipoR1             and AdipoR2) and leptin receptor (Ob-Rb) were detected by quantitative real-time             RT-PCR (qRT-PCR) in six endometrial cancer cell lines. Leptin (1 µg/ml) treatment             stimulated SPEC-2 cell proliferation by inducing cell cycle arrest and apoptosis,             while Acrp30 (10 µg/ml) treatment inhibited the growth of SPEC-2 cells. Importantly,             Acrp30 was able to inhibit leptin-induced SPEC-2 cell proliferation. Leptin promoted             SPEC-2 cell invasion in a Matrigel transwell assay, while Acrp30 partly suppressed             the invasion stimulated by leptin. To investigate the molecular mechanism underlying             this phenomenon, we monitored the AMPK and JAK/STAT3 signaling pathways by western             blotting and cell immunofluorescence. Acrp30 reduced leptin-induced STAT3 phosphorylation             and nuclear translocation via activation of the MAPK pathway. AG490 (JAK/STAT3             inhibitor) reduced MMP-2 and MMP-9 protein levels in cells treated with leptin,             while IL-6 (JAK/STAT3 stimulator) and Compound C (AMPK inhibitor) elevated MMP-2             and MMP-9 protein levels in cells treated with Acrp30. In conclusion, we demonstrated             that Acrp30 effectively reversed the invasion stimulated by leptin, and AMPK and             JAK/STAT3 pathways mediated the invasive phenotype of SPEC-2 cells.
International Peace Maternity and Child Health Hospital, Shanghai Jiao Tong University, Shanghai 200030, PR China.
Xiaomei
X
Wu
Qin
Q
Yan
Zhenbo
Z
Zhang
Guiqiang
G
Du
Xiaoping
X
Wan
D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D052242:Adiponectin / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation; D016889:Endometrial Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D053612:Janus Kinases / Q000378:metabolism*; D020738:Leptin / Q000494:pharmacology*; D008565:Membrane Proteins / Q000378:metabolism*; D009362:Neoplasm Metastasis; D021381:Protein Transport / Q000187:drug effects; D054419:Receptors, Adiponectin / Q000235:genetics; D054411:Receptors, Leptin / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
C475418:ADIPOR1 protein, human; C475420:ADIPOR2 protein, human; D052242:Adiponectin; C515671:CDC42SE2 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D020738:Leptin; D008565:Membrane Proteins; D054419:Receptors, Adiponectin; D054411:Receptors, Leptin; D050796:STAT3 Transcription Factor; D053612:Janus Kinases; D055372:AMP-Activated Protein Kinases