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

Abstract

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 ¼ 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 ¼ 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.

Identification of Circadian Determinants of Cancer Chronotherapy through In Vitro Chronopharmacology and Mathematical Modeling

“…Moreover, irinotecan cytotoxicity appeared to be positively correlated to the expression level of clock gene BMAL1, both in clock-proficient and in clock-deficient cells. In contrast, the cytotoxicity of oxaliplatin, another effective anticancer drug against colorectal cancer, reportedly displayed a negative correlation with BMAL1 expression level (33). Taken together, the findings suggest that BMAL1 tumor expression could help select the most effective drug for a given patient.…”

The Role of Biological Clock in Gynecologic Cancer

“…These findings provide a mechanistic foundation for the delayed onset of tumorigenesis in clock-disrupted p53 mutant mice, giving a note of optimism in treating cancers associated with p53 mutation [37]. In humans, the expression level of TIM was higher in the tumor tissue of colorectal cancer patients, while the overexpression of the circadian clock gene BMAL1 increases sensitivity to oxaliplatin in patients with colorectal cancer [38,39]. Mazzoccoli evaluated chronodisruption in lung cancer; actually, he found that in patients with lung cancer, GH, IGF1, TRH, TSH, FT4, cortisol and IL2 values did not show rhythmic variation [40].…”

DNA damage and the circadian clock

“…High BMAL1 levels in the primary tumour in pa ents with colorectal cancer were associated with longer overall survival (>1.5 mes) than the overall survival rates in pa ents with tumours with low BMAL1 levels [36]. Similarly, the progression-free survival in pa ents with colorectal tumours expressing BMAL1 at high levels was es mated to be almost twice as long as the progression-free survival in pa ents with tumours expressing BMAL1 at low levels [36].…”

“…Timing of an cancer therapy around the circadian cycle may increase its efficacy and minimise the associated adverse effects [36] (for more informa on also see below).…”