Search of inhibitors effective in suppressing the altered invasiveness of irradiated cancer cell line.

Tumor cells invade by two modes of motility—mesenchymal and amoeboid. Tumor cells with the mesenchymal mode of motility are known to use proteolytic enzymes to create a path to move through the ECM. In contrast, cells with the amoeboid mode of motility, which are rounded, exhibit a protease-independent mechanism of invasion; this mechanism is based on actomyosin contractility. Evidence shows that some cells can shift between these two modes of motility, depending on the environmental conditions; this may limit the effectiveness of therapeutic agents, such as protease inhibitors, which are directed at inhibiting a single mode of tumor cell motility. Therefore, an understanding of cancer cell motility is critical for the effective use of inhibitors. Irradiation alters the invasiveness of several tumor cell lines, however the effects of irradiation on the modes of motility remain unknown. Here we report that X-ray irradiation enhanced human pancreatic cancer cell lines MIAPaCa-2 and PANC-1 invasion via matrix metalloproteinase-2 (MMP-2), whereas Carbon-ion (C-ion) irradiation reduced MIAPaCa-2 invasion but increased PANC-1 invasion via serine proteases (SerP). Treatment of MMP inhibitor (MMPI) or SerP inhibitor (SerPI) failed to decrease the radiation-enhanced MIAPaCa-2 or PANC-1 invasion accompanied by mesenchymal–amoeboid transition. ROCK inhibitor plus those protease inhibitor suppressed the enhanced invasiveness, suggested that both modes of motility were significant in MIAPACa-2 and PANC-1. We further found that irradiation affects the activity of small GTPase, Rac1 and RhoA, the key factors involved in two modes of motility. Rac1 was activated in X-ray-irradiated MIAPaCa-2, whereas, both Rac1 and RhoA activities were diminished in C-ion-irradiated MIAPaCa-2. In contrast, RhoA was activated in C-ion-irradiated PANC-1. These results suggested that irradiation alters the invasive potential through protease activity, and also Rac1 and RhoA activities. Overall, the study indicated that the inappropriate use of inhibitors, i.e., the use of protease_I or ROCKI alone, may lead to the induction of invasive potential in some cell types. Therefore, the use of inhibitors of both mesenchymal and amoeboid modes of motility is the effective strategy for altered invasiveness of irradiated MIAPaCa-2 and PANC-1 invasiveness.Heavy Ion in Therapy and Space Radiation Symposium 2013 (HITSRS2013