||Effects of Irradiation on Cellular Invasiveness with Regard to Cancer Cell Heterogeneity
Fujita, Mayumi ,
Imadome, Kaori ,
Shoji, YoshimiImai, Takashi
Tumor metastasis is the major cause of cancer-related mortality. We and other groups have reported that photon irradiation enhances the invasiveness of tumor cell lines, whereas carbon-ion (C-ion) irradiation reduces invasion. However, each of these studies used only a few particular cell lines and did not demonstrate the heterogeneity of the cell lines. Heterogeneity of mutated genes among cancer cells may cause the cells to have different responses to irradiation; thus, it is necessary to use a more diverse set of cell lines to clarify the effects of irradiation on invasiveness with regard to the heterogeneity. To date, we have used 30 tumor cell lines to examine the effects of X-ray (4 Gy) or C-ion (2 Gy) irradiation on invasiveness. In contrast to X-ray irradiation, C-ion irradiation was effective in suppressing the invasion of many cell lines. Indeed, 11 cell lines showed an over 25% reduction in invasiveness. However, C-ion irradiation also enhanced the invasiveness of two cell lines. To elucidate the molecular factors involved in the irradiation-altered invasiveness, we used two pancreatic cancer cell lines, MIAPaCa-2 and PANC-1, which exhibited diminished or enhanced invasiveness after C-ion irradiation, respectively. In MIAPaCa-2, C-ion irradiation reduced the expression of GTP-Rac1 and GTP-RhoA, two master regulators of cell motility. In contrast, no reduction in GTP-Rac1 was detected in C-ion-irradiated PANC-1 cells, and GTP-RhoA levels were increased. Moreover, the reductions in GTP-Rac1 and GTP-RhoA observed in irradiated MIAPaCa-2 were recovered by treatment with a proteasome inhibitor, indicating that these proteins underwent degradation via the ubiquitin-proteasome pathway. Among the E3 ubiquitin ligases affecting Rac1, XIAP was selectively induced and was coprecipitated with GTP-Rac1 in C-ion-irradiated MIAPaCa-2. In conclusion, C-ion irradiation was effective in reducing the invasiveness of many cell lines. However, some cells were not affected, suggesting that those effects were influenced by the genomic heterogeneity. Indeed, GTP-Rac1 and GTP-RhoA expression levels were differentially regulated in MIAPaCa-2 and PANC-1. Therefore, genes affecting GTP-Rac1 and GTP-RhoA levels may be promising candidates for modulating the irradiation-dependent invasiveness of cancer cells.
15th International Congress of Radiation Research (ICRR 2015)