APPL1-Mediating Leptin Signaling Contributes to Proliferation and Migration of Cancer Cells.
Leptin has been implicated in tumorigenesis and tumor progression, particularly in obese patients. As a multifunctional adaptor protein, APPL1 (containing pleckstrin homology domain, phosphotyrosine binding domain, and a leucine zipper motif 1) plays a critical role in regulating adiponectin and insulin signaling pathways. Currently, high APPL1 level has been suggested to be related to metastases and progression of some types of cancer. However, the intercourse between leptin signaling pathway and APPL1 remains poorly understood. Here, we show that the protein levels and phosphorylation statues of APPL1were highly expressed in tissues from human hepatocellular carcinoma and triple-positive breast cancer. Leptin stimulated APPL1 phosphorylation in a time-dependent manner in both human hepatocellular carcinoma HepG2 cell and breast cancer MCF-7 cell. Overexpression or suppression of APPL1 promoted or attenuated, respectively, leptin-induced phosphorylation of STAT3, ERK1/2, and Akt in the cancer cells, accompanied with enhanced or mitigated cell proliferation and migration. In addition, we identified that APPL1 directly bound to both leptin receptor and STAT3. This interaction was significantly enhanced by leptin stimulation. Our results suggested that APPL1 positively mediated leptin signaling and promoted leptin-induced proliferation and migration of cancer cells. This finding reveals a novel mechanism by which leptin promotes the motility and growth of cancer cells.
Department of Hepatobiliary & Laparascopic Surgery, Wuhan University Renmin Hospital, Wuhan, 430060, China.
Youming
Y
Ding
Department of Pathology & Pathophysiology, Wuhan University School of Basic Medical Sciences, Wuhan, 430071, China.
Yingkang
Y
Cao
Department of Hepatobiliary & Laparascopic Surgery, Wuhan University Renmin Hospital, Wuhan, 430060, China.
Bin
B
Wang
Department of Hepatobiliary & Laparascopic Surgery, Wuhan University Renmin Hospital, Wuhan, 430060, China.
Lei
L
Wang
Department of Pathology & Pathophysiology, Wuhan University School of Basic Medical Sciences, Wuhan, 430071, China.
Yemin
Y
Zhang
Department of Pathology & Pathophysiology, Wuhan University School of Basic Medical Sciences, Wuhan, 430071, China.
Deling
D
Zhang
Department of Hepatobiliary & Laparascopic Surgery, Wuhan University Renmin Hospital, Wuhan, 430060, China.
Xiaoyan
X
Chen
Department of Pathology & Pathophysiology, Wuhan University School of Basic Medical Sciences, Wuhan, 430071, China.
Mingxin
M
Li
Department of Pathology & Pathophysiology, Wuhan University School of Basic Medical Sciences, Wuhan, 430071, China.
Changhua
C
Wang
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology*; D049109:Cell Proliferation / Q000502:physiology*; D056945:Hep G2 Cells; D006801:Humans; D007328:Insulin / Q000378:metabolism; D020738:Leptin / Q000378:metabolism*; D008113:Liver Neoplasms / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000502:physiology; D061986:MCF-7 Cells; D009765:Obesity / Q000378:metabolism; D010766:Phosphorylation / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D054411:Receptors, Leptin / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology
C464801:APPL1 protein, human; D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D007328:Insulin; D020738:Leptin; D054411:Receptors, Leptin; D050796:STAT3 Transcription Factor; D051057:Proto-Oncogene Proteins c-akt