KiSS1 suppresses metastasis in human ovarian cancer via inhibition of protein kinase C alpha.
Metastasis is a vital target for cancer treatment, since the majority of cancer patients die from metastatic, rather than the primary disease. KiSS1 has been identified as a metastasis suppressor gene in melanoma and breast carcinomas. We show here that KiSS1 is also a metastasis suppressor in human ovarian cancer. Overexpression of KiSS1 in ovarian cancer cells inhibits cell migration induced by serum or lysophosphatidic acid (LPA), and colonization in soft agar, but not cell proliferation, representing the characteristics of a metastasis suppressor gene. Furthermore, using an experimental metastatic mouse model, we show that expression of KiSS1 in SKOV3 ovarian cancer cells suppresses >50% metastatic colonization in mice (P < 0.0001). We find that activating protein kinase C (PKC) reverses about 80% of the inhibited cell migration induced by KiSS1, while down-regulation of PKCalpha with shRNA restores KiSS1 effect, providing evidence that inhibiting PKCalpha may be an important mechanism of the effect of KiSS1. These results suggest that KiSS1 is a metastasis suppressor of ovarian cancer and may be a potential molecular target for the treatment.
Jiang
Ying
Y
Department of Cancer Biology, The Lerner Research Institute, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA.
Berk
Michael
M
Singh
Lisam Shanjukumar
LS
Tan
Haiyan
H
Yin
Lihong
L
Powell
C Thomas
CT
Xu
Yan
Y
D000818:Animals; D002465:Cell Movement / Q000502:physiology; D049109:Cell Proliferation; D015536:Down-Regulation; D005260:Female; D006801:Humans; D059648:Kisspeptins; D008246:Lysophospholipids / Q000502:physiology; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis / Q000503:physiopathology*; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000503:physiopathology*; D051571:Protein Kinase C-alpha / Q000037:antagonists & inhibitors / Q000502:physiology*; D011506:Proteins / Q000502:physiology*; D014183:Transplantation, Heterologous; D025521:Tumor Suppressor Proteins
C106628:KISS1 protein, human; D059648:Kisspeptins; D008246:Lysophospholipids; D011506:Proteins; D025521:Tumor Suppressor Proteins; D051571:Protein Kinase C-alpha; C032881:lysophosphatidic acid