Overexpression of the Circadian Clock Gene Bmal1 Increases Sensitivity to Oxaliplatin in Colorectal Cancer

Nov 27, 2013Clinical cancer research : an official journal of the American Association for Cancer Research

Higher levels of the body’s clock gene Bmal1 may increase colorectal cancer’s response to the chemotherapy drug oxaliplatin

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Abstract

High Bmal1 levels in primary tumors are associated with significantly longer overall survival in colorectal cancer patients, averaging 27 months compared to 19 months for those with low levels.

Bmal1 overexpression inhibits colorectal cancer cell proliferation and enhances sensitivity to oxaliplatin in three cell lines and in a mouse model.
Patients with high Bmal1 expression experience significantly longer progression-free survival (11 months) compared to those with low expression (5 months).
The effect of Bmal1 is linked to its regulation of cell cycle arrest in the G2-M phase through the activation of the ATM pathway.
Immunohistochemical analysis indicates that Bmal1 expression levels in tumors may serve as a potential prognostic biomarker in colorectal cancer.

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PURPOSE: The circadian clock gene Bmal1 is involved in cancer cell proliferation and DNA damage sensitivity. The aim of this study was to explore the effect of Bmal1 on oxaliplatin sensitivity and to determine its clinical significance in colorectal cancer.

EXPERIMENTAL DESIGN: Three colorectal cancer cell lines, HCT116, THC8307 and HT29, were used. The Bmal1-mediated control of colorectal cancer cell proliferation was tested in vitro and in vivo. MTT and colony formation assays were performed to determine the sensitivity of colorectal cancer cells to oxaliplatin. Flow cytometry was used to examine changes in the cell-cycle distribution and apoptosis rate. Proteins expressed downstream of Bmal1 upon its overexpression were determined by Western blotting. Immunohistochemistry was used to analyze Bmal1 expression in 82 archived colorectal cancer tumors from patients treated with oxaliplatin-based regimens.

RESULTS: Bmal1 overexpression inhibited colorectal cancer cell proliferation and increased colorectal cancer sensitivity to oxaliplatin in three colorectal cancer cell lines and HCT116 cells model in vivo. Furthermore, the overall survival of patients with colorectal cancer with high Bmal1 levels in their primary tumors was significantly longer than that of patients with low Bmal1 levels (27 vs. 19 months; P = 0.043). The progression-free survival of patients with high Bmal1 expression was also significantly longer than that of patients with low Bmal1 expression (11 vs. 5 months; P = 0.015). Mechanistically, the effect of Bmal1 was associated with its ability to regulate G2-M arrest by activating the ATM pathway.

CONCLUSION: Bmal1 shows the potential as a novel prognostic biomarker and may represent a new therapeutic target in colorectal cancer.

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Overexpression of the Circadian Clock Gene Bmal1 Increases Sensitivity to Oxaliplatin in Colorectal Cancer

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