K-ras mutation is involved in
cancer progression including invasion and migration, but the underlying mechanism is not yet clear.
Cathepsin L is a lysosomal
cysteine protease and has recently been associated with invasion and migration in human
cancers when it is overexpressed. Our recent studies have shown that ionizing radiation (IR) enhanced expression of
cathepsin L and increased invasion and migration of
tumor cells, but the molecular mechanism is still unclear. In the present study, the effects of K-ras mutation and IR induced invasion and migration of
lung cancer as well as the underlying mechanisms were investigated both in vitro and in vivo. Firstly, the levels of
cathepsin L and epithelial mesenchymal transition (EMT) marker
proteins remarkably changed in A549 (K-ras mutant) after irradiation compared with H1299 (K-ras wild), thereby promoting invasion and migration. Additionally,
cathepsin L and its downstream
transcription factor CUX1/p110 were increased after irradiation in A549 transfected with CUX1/p200, and the proteolytic processing of CUX1 by
cathepsin L was remarkably increased after co-transfection of CUX1/p200 and
cathepsin L-lentivirus in H1299. In addition, delivery of a mutant K-ras (V12) into HEK 293 cells stimulated EMT after irradiation due to the accumulation of
cathepsin L. Moreover, mutated K-ras was associated with IR-induced
cathepsin L and EMT in BALB/c nude mice. Finally, the level of
cathepsin L expression was higher in samples carrying a K-ras mutation than in wild-type K-ras samples and the mesenchymal markers were upregulated in the samples of mutant K-ras, whereas the epithelial marker
E-cadherin was downregulated in non-small cell
lung cancers tissues. In conclusion, the findings demonstrated that mutated K-ras promotes
cathepsin L expression and plays a pivotal role in EMT of human
lung cancer. The regulatory effect of IR-induced
cathepsin L on
lung cancer invasion and migration was partially attributed to the
Cathepsin L /CUX1-mediated EMT signaling pathway. This study will provide
cathepsin L as a potential target for
tumor therapy.