Collapsin response mediator protein 4 enhances the radiosensitivity of colon cancer cells through calcium-mediated cell signaling

Radiation therapy is an effective treatment against various types of cancer, but some radiation-resistant cancer cells remain a major therapeutic obstacle; thus, understanding radiation resistance mechanisms is essential for cancer treatment. In this study, we established radiation-resistant colon cancer cell lines and examined the radiation-induced genetic changes associated with radiation resistance. Using RNA-sequencing analysis, collapsin response mediator protein 4 (CRMP4) was identified as the candidate gene associated with radiation sensitivity. When cells were exposed to radiation, intracellular Ca(2+) influx, collapse of mitochondrial membrane potential, and cytochrome c release into the cytosol were increased, followed by apoptosis induction. Radiation treatment- or Ca(2+) ionophore A23187-induced apoptosis was significantly inhibited in CRMP4-deficient cells, including radiation-resistant or CRMP4-shRNA cell lines. Furthermore, treatment of CRMP4-deficient cells with low levels (<5 µM) of BAPTA-AM, a Ca(2+) chelator, resulted in radiation resistance. Conversely, Ca(2+) deficiency induced by a high BAPTA-AM concentration (>10 µM) resulted in higher cell death in the CRMP4-depleted cells compared to CRMP4-expressing control cells. Our results suggest that CRMP4 plays an important role in Ca(2+)-mediated cell death pathways under radiation exposure and that CRMP4 may be a therapeutical target for colon cancer treatment.