Involvement of Wee1 in the Circadian Rhythm–Dependent Intestinal Damage Induced by Docetaxel

Abstract

Docetaxel, a semisynthetic taxane, is effective for the treatment of some solid cancers; however, docetaxel-induced intestinal damage leads to poor prognosis in some patients. Although such adverse effects have been reported to depend on the dosing-time of docetaxel, the mechanisms involved remain unclear. Wee1 expression is controlled by the clock gene complex, clock/bmal1, and contributes to cell-cycle progression. The present study was undertaken to evaluate the potential role of Wee1 in the circadian rhythm-dependent profile of docetaxel. Male mice were maintained under a 12-hour light/ dark cycle. Intestinal damage after repeated dosing of docetaxel (20 mg/kg) for 3 weeks was more severe at 14 hours after light on (HALO) than at 2 HALO. The intestinal protein expressions of Wee1, phosphorylated CDK1, and cleaved Caspase-3 were higher in the 14-HALO group than in the 2-HALO group, whereas that of survivin was lower in the 14-HALO group. Thus, it is speculated that elevated Wee1 expression inhibited CDK1 activity more by phosphorylation, which in turn caused the lower expression of survivin and consequently more activated Caspase-3 in the 14-HALO group. There were no significant differences in plasma docetaxel concentrations between the 2-and 14-HALO groups. Bindings of CLOCK and BMAL1 to the E-box regions at the wee1 gene promoter were not altered by docetaxel treatment at 2 and 14 HALO. These findings suggest that Wee1 is directly or indirectly involved in the mechanism of the circadian rhythm-dependent changes in docetaxel-induced intestinal damage. However, the mechanism for a circadian rhythm-dependent change in intestinal Wee1 expression by docetaxel remains to be determined.

Wee1 is a novel independent prognostic marker of poor survival in post-chemotherapy ovarian carcinoma effusions

“…This hypothesis is supported by recent data that overexpression of Wee1 is commonly found in cisplatin-resistant carcinoma cells [34]. Likewise, docetaxel has been shown to increase Wee1 expression in rat intestinal mucosa [35]. A number of in vitro as well as in vivo studies have demonstrated a synergistic treatment response when Wee1 inhibition is combined with DNA-damaging agents, including, recently, in malignant mesothelioma [36], a cancer which affects the serosal cavities and shares morphological, immunohistochemical and genetic characteristics with serous OC [17].…”

Circadian oscillation in primary cilium length by clock genes regulates fibroblast cell migration

“…Several clock genes act as gatekeepers in the cell cycle (Matsuo et al , 2003). BMAL1/CLOCK controls the cell cycle by directly regulating the expression of WEE1, an inhibitor of CDC2/cyclin B1 (Obi‐Ioka et al , 2013; Farshadi et al , 2019). PER1 inhibits cyclin D1 (Fu et al , 2016).…”

Circadian oscillation in primary cilium length by clock genes regulate fibroblast cell migration

“…Several clock genes act as gatekeepers in the cell cycle (Matsuo et al , 2003). BMAL1/CLOCK controls the cell cycle by directly regulating the expression of WEE1, an inhibitor of CDC2/cyclin B1 (Farshadi et al , 2019; Obi-Ioka et al , 2013). PER1 inhibits Cyclin D1 (Fu et al , 2016).…”