Phosphoinositide 3-kinase inhibitor (wortmannin)  inhibits pancreatic cancer cell motility and migration  induced by hyaluronan in vitro and peritoneal  metastasis in vivo.
In order to block peritoneal metastasis of pancreatic cancer cells, we have attempted to block the signal transduction pathway involving hyaluronan (HA), Src, phosphoinositide 3-kinase (PI3K) and Akt. We examined the effects of Src, PI3K and Akt inhibitors on pancreatic cancer cell motility, invasion and metastasis. The pancreatic cancer cell line SW1990, known to cause peritoneal metastasis efficiently in nude mice, was used in this study. SW1990 cells were stimulated by HA to induce Akt phosphorylation. Then, the inhibitory effects of PI3K and Src kinase inhibitors were examined. Cell motility and cell migration assays were adopted to assess the cancer cell motility and its migration capability. We also examined the therapeutic efficacies of PI3K inhibitor wortmannin on peritoneal metastasis of SW1990 cells in the nude mouse model. Stimulation of SW1990 cells by HA markedly induced the Src-PI3K-Akt signaling, thus enhancing cancer cell motility and its migration. Significantly, we found that wortmannin could exert marked inhibition of the peritoneal metastasis of SW1990 in nude mice in vivo. These findings indicate that the PI3K-Akt signaling pathway plays an essential role in peritoneal metastasis and PI3K inhibitors such as wortmannin can be novel modalities to prevent peritoneal metastasis of invasive cancers such as pancreatic cancer.
Teranishi
Futoshi
F
Department of Molecular and Cellular Biology, Nagoya City University, Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, 467-8601, Japan.
Takahashi
Naoko
N
Gao
Nan
N
Akamo
Yoshimi
Y
Takeyama
Hiromitsu
H
Manabe
Tadao
T
Okamoto
Takashi
T
D000730:Androstadienes / Q000627:therapeutic use*; D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D006801:Humans; D006820:Hyaluronic Acid / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D010534:Peritoneal Neoplasms / Q000517:prevention & control / Q000556:secondary*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors; D000077191:Wortmannin; D023041:Xenograft Model Antitumor Assays; D019061:src-Family Kinases / Q000037:antagonists & inhibitors
D000730:Androstadienes; D004791:Enzyme Inhibitors; D000081082:Phosphoinositide-3 Kinase Inhibitors; D006820:Hyaluronic Acid; D019061:src-Family Kinases; D051057:Proto-Oncogene Proteins c-akt; D000077191:Wortmannin