title: X-ray irradiation and Rho-kinase inhibitor additively induce invasiveness of the cells of the pancreatic cancer line, MIAPaCa-2, which exhibits mesenchymal and amoeboid motility.
abstract: Tumor cells can migrate and invade tissue by two modes of motility: mesenchymal and amoeboid. X-ray or γ-ray irradiation increases the invasiveness of tumor cells with mesenchymal motility through the induction of matrix metalloproteinases (MMP), and this increase is suppressed by MMP inhibitors (MMPI). However, the effects of X-ray or γ-ray irradiation on the invasiveness of tumor cells with amoeboid motility remain unclear. We investigated the effect of irradiation on amoeboid motility by using cells of the human pancreatic cancer line, MIAPaCa-2, which exhibits both modes of motility. The X-ray-induced invasiveness of MIAPaCa-2 cells was associated with the upregulation of MMP2 at both the RNA and protein levels and was inhibited by MMPI treatment. Amoeboid-mesenchymal transition was slightly induced after irradiation. The MMPI treatment caused mesenchymal-amoeboid transition without significant increase in invasiveness, while the ROCK inhibitor (ROCKI) stimulated amoeboid-mesenchymal transition and enhanced invasiveness under both non-irradiated and irradiated conditions. This ROCKI-induced transition was accompanied by the upregulation of MMP2 mRNA and protein. Exposure to both irradiation and ROCKI further enhanced MMP2 expression and had an additive effect on the invasiveness of MIAPaCa-2 cells. Additionally, exposure to MMPI led to significant suppression of both radiation-induced and the basal invasiveness of MIAPaCa-2 cells. This suggests that ROCKI treatment, especially with concomitant X-ray irradiation, can induce invasion of cancer cells and should be used only for certain types of cancer cells. Simultaneous use of inhibitors, ROCKI and MMPI may be effective in suppressing invasiveness under both X-ray-irradiated and non-irradiated conditions.
authors.affiliation: RadGenomics Research Group, Research Center for Charged Particle Therapy, National Institute of Radiological Sciences, Chiba, Japan.
authors.forename: Mayumi
authors.initials: M
authors.lastname: Fujita
authors.forename: Yoshimi
authors.initials: Y
authors.lastname: Otsuka
authors.forename: Shigeru
authors.initials: S
authors.lastname: Yamada
authors.forename: Mayumi
authors.initials: M
authors.lastname: Iwakawa
authors.forename: Takashi
authors.initials: T
authors.lastname: Imai
mesh_terms: D000656:Amoeba / Q000187:drug effects* / Q000528:radiation effects*; D015153:Blotting, Western; D002448:Cell Adhesion; D002465:Cell Movement / Q000187:drug effects*; D004151:Dipeptides / Q000494:pharmacology; D006801:Humans; D061965:Matrix Metalloproteinase Inhibitors; D008648:Mesoderm / Q000187:drug effects / Q000473:pathology* / Q000528:radiation effects; D009361:Neoplasm Invasiveness; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000473:pathology* / Q000532:radiotherapy; D011480:Protease Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D014965:X-Rays; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors* / Q000494:pharmacology
chemical_list: D004151:Dipeptides; D061965:Matrix Metalloproteinase Inhibitors; C078131:N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide; D011480:Protease Inhibitors; D012333:RNA, Messenger; C515851:ROCK1 protein, human; D054460:rho-Associated Kinases