Targeting Valosin-Containing Protein Enhances the Efficacy of Radiation Therapy in Esophageal Squamous Cell Carcinoma.

Overcoming resistance to radiation is a great challenge in cancer therapy. Here we highlight that targeting valosin-containing protein (VCP) improves radiation sensitivity in esophageal squamous cell carcinoma (ESCC) cell lines and show the potential of using VCP as a prognosis marker in locally advanced ESCC treated with radiation therapy. ESCC cell lines with high VCP expression were treated with VCP inhibitor combined with radiotherapy. Cell proliferation, colony formation, cell death, and the endoplasmic reticulum (ER) stress signaling were evaluated. Moreover, patients with newly diagnosed locally advanced ESCC who were treated with radiotherapy were analyzed. Immunohistochemistry was used to detect the expression of VCP. The correlation between overall survival (OS) and VCP was investigated. ESCC cells treated with VCP inhibitor and radiotherapy showed attenuated cell proliferation, colony formation and enhanced apoptosis. Further investigation showed this combined strategy activated the ER stress signaling, involved in unfolded protein response (UPR) and inhibited the endoplasmic reticulum associated degradation (ERAD) pathway. Clinical analysis revealed a significant survival benefit in the low VCP expression group. Targeting VCP resulted in antitumor activity and enhanced the efficacy of radiation therapy in ESCC cells in vitro. VCP is a promising and novel target. In patients of locally advanced ESCC who received radiotherapy, VCP can be considered as a useful prognostic indicator of OS. VCP inhibitors could be developed for use as effective cancer therapies, in combination with radiation therapy.