Journal Article Carbon-ion irradiation suppresses migration and invasiveness of human pancreatic carcinoma cells MIAPaCa-2 via Rac1 and RhoA degradation

Fujita, Mayumi  ,  Imadome, Kaori  ,  Shoji, Yoshimi  ,  Isozaki, Teturou  ,  Endo, Satoshi  ,  Yamada, Shigeru  ,  Imai, Takashi

93 ( 1 )  , pp.173 - 180 , 2015-05 , Tarrytown Ny : Elsevier Science Inc
PurposeThis study investigated the mechanisms underlying the inhibition of cancer cell migration and invasion by carbon (C)-ion irradiation.Methods and MaterialsHuman pancreatic cancer cells MIAPaCa-2, AsPC-1, and BxPC-3 were treated by X-ray (4 Gy) or C-ion (0.5, 1, 2, or 4 Gy) irradiation, and their migration and invasion were assessed 2 days later. The levels of GTP-bound Rac1 and RhoA were determined by the active GTPase pull-down assay with or without a proteasome inhibitor, and the binding of E3 ubiquitin ligase to GTP-bound Rac1 was examined by immunoprecipitation.ResultsC-ion irradiation reduced the levels of GTP-bound Rac1 and RhoA, two major regulators of cell motility, in MIAPaCa-2 cells and GTP-bound Rac1 in AsPC-1 and BxPC-3 cells. Proteasome inhibition reversed the effect, indicating that C-ion irradiation induced Rac1 and RhoA degradation via the ubiquitin (Ub)-proteasome pathway. E3 Ub ligase X-linked inhibitor of apoptosis protein (XIAP) which directly targets Rac1, was selectively induced in C-ion irradiated MIAPaCa-2 cells and co-precipitated with GTP-bound Rac1 in C-ion-irradiated cells, which was associated with Rac1 ubiquitination. Cell migration and invasion reduced by C-ion radiation were restored by siRNA-mediated XIAP knockdown, indicating that XIAP is involved in C-ion-induced inhibition of cell motility.ConclusionIn contrast to X-ray irradiation, C-ion treatment inhibited the activity of Rac1 and RhoA in MIAPaCa-2 cells and Rac1 in AsPC-1 and BxPC-3 cells via Ub-mediated proteasomal degradation, thereby blocking the motility of these pancreatic cancer cells.

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