MG132 enhances the radiosensitivity of lung cancer cells in vitro and in vivo

Abstract

Radiotherapy is a common treatment modality for lung cancer, however, radioresistance remains a fundamental barrier to attaining the maximal efficacy. Cancer cells take advantage of the ubiquitin-proteasome system (UPS) for increased proliferation and decreased apoptotic cell death. MG132 (carbobenzoxyl-leucinyl-leucinyl-leucinal‑H), a specific and selective reversible inhibitor of the 26S proteasome, has shown anticancer effect in multiple types of cancers. Previously, we have reported that MG132 enhances the anti‑growth and anti-metastatic effects of irradiation in lung cancer cells. However, whether MG132 can enhance the radiosensitivity in lung cancer cells in vitro and in vivo is still unknown. In this study, we found that MG132 increased apoptosis and dicentric chromosome ratio of A549 and H1299 cells treated by irradiation. Radiation-induced NF-κB expression and IκBα phosphorylation was attenuated in MG132 plus irradiation-treated cells. The in vivo model of H1299 xenografts of nude mice showed that the tumor size of MG132 plus irradiation treated xenografts was smaller than that of irradiation, MG132 or the control group. Moreover, MG132 plus irradiation group showed significant reduced Ki67 expression. Taken together, these results demonstrate that MG132 enhances the radiosensitivity through multiple mechanisms in vitro and in vivo.

Positioning of proteasome inhibitors in therapy of solid malignancies

“…Combination therapies of BTZ with paclitaxel/carboplatin/radiation, irinotecan, radiation and the HDAC inhibitor vorinostat showed promising results in NSCLC therapy [ 42 , 82 – 85 ]. However, cisplatin with, or without gemcitabine, did not improve the efficacy of BTZ [ 86 , 87 ].…”

“…Moreover, proteasome inhibition disrupts radioresistance mechanisms such as NFkB activation, loss of p53 and DNA DSBs repair [ 82 , 91 ]. These effects provide a rationale for synergism of BTZ with radiotherapy in lung cancer [ 82 , 85 , 91 ].…”

Control of Hedgehog Signalling by the Cilia-Regulated Proteasome

“…The relationship between the cilia-regulated proteasome and HH signalling is essential for homeostasis and embryonic development in vertebrates. For example, an alteration of proteasomal activity is thought to be involved in the development of cancer [ 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 ]. In this context, the cilia-regulated proteasome might have an essential role, a topic which was extensively reviewed elsewhere [ 45 ].…”

Research progress on therapeutic targeting of quiescent cancer cells

“…The ubiquitin-proteasome system (UPS) is essential for degradation of aberrantly folded proteins and short-lived proteins involved in cell cycle progression, apoptosis, and signal transduction [5,56,57]. Tumor cells utilize UPS to achieve aberrant proliferation and survival [58].…”

“…MG132 has been shown to enhance irradiation-induced apoptosis by suppressing activation of NF-jB and tumor growth [57]. However, other reports suggest that proteasome inhibition with MG-132 or bortezomib induces G0-G1 phase arrest in MM cells, resulting in lower sensitivity of tumor cells to treatment and survival [5,63].…”