Radiation-induced increase in invasive potential of human pancreatic cancer cells and its blockade by a matrix metalloproteinase inhibitor, CGS27023.
OBJECTIVE
Radiotherapy remains a major therapeutic option for patients with advanced pancreatic cancer. Nevertheless, the effects of irradiation on malignant biological behaviors (e.g., migration and invasion of cancer cells) have yet to be clarified. Thus, we conducted an in vitro study to investigate the radiation-induced alterations around cell migration and invasion capacity.


METHODS
Three cell lines from human pancreatic cancer were included in the study. gamma-radiation was used for irradiation treatment. Cell migration and invasion ability were evaluated by Transwell migration assay and Matrigel invasion assay. The activity of MMP-2 and 9, and expression of urokinase-type plasminogen activator were investigated with gelatin zymography and immunoblot, respectively.


RESULTS
Irradiation enhances invasive potential in some pancreatic cancer cells, whereas it significantly inhibits cell proliferation and migration. This hitherto unknown biological effect of irradiation involves enhanced matrix metalloproteinase (MMP)-2 activity. Consequently, simultaneous administration of an MMP inhibitor, CGS27023A, suppresses the radiation-enhanced invasion through blockade of transition of MMP-2 from latent type to active type.


CONCLUSIONS
Because radiation may increase invasion ability through activating MMP proteolytic system, simultaneous administration of the MMP inhibitor during radiotherapy could be a potent adjuvant therapeutic approach to improve the efficacy of radiotherapy for pancreatic cancer.
Qian
Li-Wu
LW
Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
Mizumoto
Kazuhiro
K
Urashima
Taro
T
Nagai
Eishi
E
Maehara
Naoki
N
Sato
Norihiro
N
Nakajima
Motowo
M
Tanaka
Masao
M
D002455:Cell Division / Q000187:drug effects / Q000528:radiation effects; D002465:Cell Movement / Q000187:drug effects* / Q000528:radiation effects; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000473:pathology / Q000532:radiotherapy; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000201:enzymology / Q000528:radiation effects; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism
D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D061965:Matrix Metalloproteinase Inhibitors; C115088:CGS 27023; D014568:Urokinase-Type Plasminogen Activator; D020778:Matrix Metalloproteinase 2