Leptin promotes invasiveness of murine renal cancer cells via extracellular signal-regulated kinases and rho dependent pathway.
OBJECTIVE
Obesity is a significant risk factor for renal cell carcinoma. The adipocyte derived cytokine leptin, which controls body weight homeostasis through food intake and energy expenditure, recently provided a potential link between obesity and cancer development. We examined whether leptin promotes the invasiveness of renal cancer cells and we investigated its underlying signaling pathway.


METHODS
Leptin receptor expression in the 6 human renal cancer cell lines Caki-1, ACHN, 769P, A498, SKRC44 and SKRC49, and in the murine renal cancer cell line Renca was examined by reverse transcriptase-polymerase chain reaction and Western blotting. The effect of leptin on renal cancer cell invasiveness was assessed by the invasion of cells through Matrigel coated Transwell inserts. Leptin induced intracellular signaling was examined by Western blotting.


RESULTS
Leptin receptor was detected in all renal cancer cells examined at the mRNA and protein levels. Leptin increased Renca cell invasiveness at 1 ng/ml (p < 0.05). There was up to 3-fold invasiveness compared to untreated cells at 100 ng/ml with the activation of extracellular signal-regulated kinases and rho guanosine triphosphatase (p < 0.01). Leptin induced activation of rho guanosine triphosphatase was inhibited not only by the rho kinase inhibitor Y27632, but also by the MEK1 inhibitor PD98059, of which each inhibited leptin induced invasion of Renca cells (p < 0.01).


CONCLUSIONS
Leptin promoted the invasiveness of murine renal cancer cells via extracellular signal-regulated kinases and rho guanosine triphosphatase dependent pathways. Rho guanosine triphosphatase was a downstream effector of extracellular signal-regulated kinases in leptin induced invasion. Leptin signaling could have a key role in renal cell carcinoma invasion.
Horiguchi
Akio
A
Department of Urology, National Defense Medical College, Saitama, Japan. impreza@cb3.so-net.ne.jp
Sumitomo
Makoto
M
Asakuma
Junichi
J
Asano
Takako
T
Zheng
Rong
R
Asano
Tomohiko
T
Nanus
David M
DM
Hayakawa
Masamichi
M
D000818:Animals; D002292:Carcinoma, Renal Cell / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology*; D007680:Kidney Neoplasms / Q000378:metabolism / Q000473:pathology*; D020738:Leptin / Q000502:physiology*; D020935:MAP Kinase Signaling System / Q000502:physiology*; D051379:Mice; D009361:Neoplasm Invasiveness; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D054411:Receptors, Leptin; D020741:rho GTP-Binding Proteins / Q000378:metabolism; D054460:rho-Associated Kinases
D047908:Intracellular Signaling Peptides and Proteins; C515448:LEPR protein, human; D020738:Leptin; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D054411:Receptors, Leptin; C515447:leptin receptor, mouse; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D020741:rho GTP-Binding Proteins