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Technol Cancer Res Treat. 2016 Aug;15(4):527-34. doi: 10.1177/1533034615588197. Epub 2015 Jun 16.

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

Author information

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 zhenzhang6@hotmail.com wjf62313172@163.com.

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

PMID:
26082455
DOI:
10.1177/1533034615588197
[Indexed for MEDLINE]

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