Radiosensitization of Human Colorectal Cancer Cells by MLN4924: An Inhibitor of NEDD8-Activating Enzyme

  • Technol Cancer Res Treat. 2016 Aug;15(4):527-34. doi: 10.1177/1533034615588197.
Juefeng Wan  1 ,  Ji Zhu  1 ,  Guichao Li  1 ,  Zhen Zhang  2
Affiliations
  • 1. Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
  • 2. Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China [email protected] [email protected].
PMID: 26082455 DOI: 10.1177/1533034615588197
Abstract

Colorectal Cancer is the third most frequently diagnosed Cancer and the combination of radiation with capecitabine has been shown to achieve only 15% to 25% of pathologic complete response. This study aimed to investigate the effect of MLN4924, a potent small molecule inhibitor of SKP1-Cullin-F-box proteins E3 ubiquitin ligases, as a novel radiosensitizing agent in colorectal Cancer cells. Indeed, we found that MLN4924 effectively sensitized colorectal Cancer cells to radiation with a sensitivity-enhancement ratio of 1.61 for HT-29 cells and 1.35 for HCT-116 cells. Mechanistically, MLN4924 significantly enhanced radiation-induced G2/M arrest, Apoptosis, and DNA damage response through accumulation of p27. Knockdown of p27 via small interfering RNA partially inhibited MLN4924-induced radiosensitization, indicating a causal role played by p27. Our study suggested that MLN4924 could be further developed as a novel radiosensitizing agent against colorectal Cancer.

Keywords
MLN4924; colorectal cancer; p27; radiosensitization.
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