Phosphorylation of Cajal body protein coilin activated by UHMK1 influences the sensitivity of colon cancer cells to 5-FU

Drug resistance to 5-fluorouracil (5-FU) and recurrence after chemotherapy in colorectal cancer remain a challenge to be resolved for the improvement of patient outcomes. In the present study, we found that the application of conditioned medium (CM) derived from 5-FU-resistant colon cancer cells HCT-8/FU reduced the chemosensitivity of native HCT-8 to 5-FU, which was accompanied with the significant changes at number counts and morphology of Cajal bodys (CBs), a spherical nuclear body, dynamic exchanging constituent macromolecules (i.e., body-specific proteins and RNAs) with the nucleoplasmic space.It was shown that the disassembly and reassembly of CBs regulated by the phosphorylation of coilin, which was significantly activated by UHMK1. These led to a large number of variations of RNA alternative splicing in cells, which could contribute to the cell survival through remodeling of intracellular phenotype and transmitting preadaptive signal to adjacent cells in tumor microenvironment. Overall design: Two paired 5-FU-resistant and -sensitive colon cancer cell lines,HCT-8/FU and HCT-8, HCT-8 cultured in CM from HCT-8/FU and HCT-8 cultured in CM from HCT-8,were used in the experiments to investigate the mechanism of cell response to environmental stimulation and the cell sensitivity to 5-FU.