Targeting valosin‐containing protein enhances the efficacy of radiation therapy in esophageal squamous cell carcinoma

Abstract

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. Esophageal squamous cell carcinoma cell lines with high VCP expression were treated with VCP inhibitor combined with radiotherapy. Cell proliferation, colony formation, cell death, and 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 and VCP was investigated. Esophageal squamous cell carcinoma cells treated with VCP inhibitor and radiotherapy showed attenuated cell proliferation and colony formation and enhanced apoptosis. Further investigation showed this combined strategy activated the ER stress signaling involved in unfolded protein response, and inhibited the ER‐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. Valosin‐containing protein is a promising and novel target. In patients with locally advanced ESCC who received radiotherapy, VCP can be considered as a useful prognostic indicator of overall survival. Valosin‐containing protein inhibitors could be developed for use as effective cancer therapies, in combination with radiation therapy.

Valosin-Containing Protein, a Calcium-Associated ATPase Protein, in Endoplasmic Reticulum and Mitochondrial Function and Its Implications for Diseases

“…Based on these results, VCP is now considering as an important target for cancer treatment. It has been shown that the inhibition of VCP is able to induce proteotoxic stress and apoptosis in cancer cells, and improve radiation sensitivity in ESCC [64]. One of the VCP inhibitors, CB-5083, is the first selective VCP inhibitor to show preclinical effects [13].…”

<p>The Evolving Role of Disulfiram in Radiobiology and the Treatment of Breast Cancer</p>

“…Radiosensitizers are compounds that make tumor cells more vulnerable to radiotherapy. 9 The search for an effective and non-toxic radiosensitizer was a major concern in radiobiologists. DSF was a drug that capable of overcoming radiation resistance of cancer cells in the following ways: formed a complex with metal ions, elevated reactive oxygen species levels, inhibited the growth of cancer stem cells, and suppressed the activity of ubiquitin-proteasome system.…”

“…8 The misfolded protein degradation pathway played a crucial role in tumor cell radiation resistance. 9 The cellular mechanisms of DSF in inducing cancer cell apoptosis have been well elaborated. Indeed, many studies demonstrated the process of DSF metabolized to diethyldithiocarbamate (DTC), DTC has antioxidant effects and can be served as a radioprotector in normal tissues; in addition, DSF was capable of enhancing radiosensitivity of breast cancer cells in number of alternative ways.…”

A covalent p97/VCP ATPase inhibitor can overcome resistance to CB-5083 and NMS-873 in colorectal cancer cells

“…NMS-873 inhibited the ERAD pathway and led to the accumulation of misfolded proteins in the ER. [29] UPCDC30245 is another allosteric p97 inhibitor with an IC 50 of 27 nM, which reversibly binds at the interface of the D1 and D2 domains as determined by cryo-electron microscopy [30]. Eeyarestatin I (EerI) serves as a prodrug to convert the 5-nitrofuran-2-yl (NFC) group into a reactive metabolite involved in inhibition of p97-dependent protein degradation in cells even though the exact mechanism of the active metabolite still remains unknown [31,32].…”