Blocking on the CXCR4/mTOR signalling pathway induces the anti-metastatic properties and autophagic cell death in peritoneal disseminated gastric cancer cells.
Patients with advanced gastric carcinoma, especially peritoneal dissemination, have a poor prognosis even after any treatment. Chemokines are now known to play an important role in cancer growth and metastasis. We recently reported that the chemokine CXCL12 plays an important role in the development of peritoneal carcinomatosis from gastric carcinoma. In this study, we investigated signalling pathway involved in the peritoneal carcinomatosis induced by chemokine CXCL12. Akt was rapidly and strongly phosphorylated by chemokine CXCL12. CXCL12 also induced the activation of p70S6K (S6K) and eukaryotic initiation factor 4E binding protein 1 (4E-BP1) included in mammalian target of rapamycin (mTOR) pathways which are located downstream of Akt, resulting in enhancements of metastatic properties such as MMP production, cell migration and cell growth in peritoneal disseminated gastric cancer, NUGC4 cells. Furthermore, mTOR inhibitor rapamycin not only drastically inhibited migration and MMP production, but also induced type II programmed cell death, autophagic cell death. In the present study, we have shown for the first time that the mTOR pathway plays a central role in the development of peritoneal carcinomatosis, and blocking this pathway induces autophagic cell death in disseminated gastric cancer. Therefore, blocking on the CXCR4/mTOR signalling pathway may be useful for the future development of a more effective therapeutic strategy for gastric cancer involved in peritoneal dissemination.
Hashimoto
Isaya
I
Department of Surgery II, Faculty of Medicine, University of Toyama, Toyama, Japan.
Koizumi
Keiichi
K
Tatematsu
Mikiko
M
Minami
Takayuki
T
Cho
Seiji
S
Takeno
Nobuhiro
N
Nakashima
Akitoshi
A
Sakurai
Hiroaki
H
Saito
Shigeru
S
Tsukada
Kazuhiro
K
Saiki
Ikuo
I
D000818:Animals; D001343:Autophagy / Q000187:drug effects / Q000502:physiology*; D015153:Blotting, Western; D054443:Cell Migration Assays; D049109:Cell Proliferation; D054377:Chemokine CXCL12 / Q000494:pharmacology; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010534:Peritoneal Neoplasms / Q000556:secondary*; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000473:pathology; D058570:TOR Serine-Threonine Kinases; D014407:Tumor Cells, Cultured
D054377:Chemokine CXCL12; D019718:Receptors, CXCR4; D011494:Protein Kinases; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases