Abstract
Regulation of diurnal and circadian rhythms and cell proliferation are coupled in all mammals, including humans. However, the molecular mechanisms by which diurnal and circadian rhythms regulate cell proliferation are relatively poorly understood. In this study, we report that tumor growth in nude rats bearing human steroid receptor-negative MCF-7 breast tumors can be significantly accelerated by exposing the rats to light at night (LAN). Under normal conditions of an alternating light/dark cycle, proliferating cell nuclear antigen (PCNA) levels in tumors were maximal in the early light phase but remained at very low levels throughout the daily 24-hour cycle period monitored. Surprisingly, PCNA was expressed in tumors continually at a high level throughout the entire 24-hour period in LAN-exposed nude rats. Daily fluctuations of Akt and mitogen activated protein kinase activation in tumors were also disrupted by LAN. These fluctuations did not track with PCNA changes, but we found that activation of the Akt stimulatory kinase phosphoinositide-dependent protein kinase 1 (PDK1) directly correlated with PCNA levels. Expression of insulin-like growth factor 1 receptor (IGF-1R), an upstream signaling molecule for PDK1, also correlated with fluctuations of PDK1/PCNA in the LAN group. In addition, circulating IGF-1 concentrations were elevated in LAN-exposed tumor-bearing nude rats. Finally, RNAi-mediated knockdown of PDK1 led to a reduction in PCNA expression and cell proliferation in vitro and tumor growth in vivo, indicating that PDK1 regulates breast cancer growth in a manner correlated with PCNA expression. Taken together, our findings demonstrate that LAN exposure can accelerate tumor growth in vivo, in part through continuous activation of IGF-1R/PDK1 signaling.
Highlights
Circadian rhythm regulation plays an important role in determining the sleep–activity and feeding cycles of all mammals, including humans
It was observed that dim light was as effective as constant light in promoting rat hepatoma [32] and human breast cancer tumor growth [27] via circadian disruption involving the suppression of melatonin production
Tissueisolated MCF-7 SRÀ tumors were implanted in 72 nude rats exposed to control lighting (12L:12D) and experimental condition (12L:12LAN-0.20 lux at night)
Summary
Circadian rhythm regulation plays an important role in determining the sleep–activity and feeding cycles of all mammals, including humans. Disruption of circadian regulation has significant adverse health consequences including the development or exacerbation of cardiovascular diseases, diabetes, depression, and cancers [2]. Behavioral conditions such as jet lag, shift work, physical activities, stress, and timing of food intake are known to disrupt circadian rhythms; the most potent factor in dysregulating normal circadian rhythms is inappropriately timed light, light at night (LAN). LAN-induced circadian disruption can profoundly alter the regulation of circadian hormones such as melatonin and cortisol, and, in turn, alter human physiology and metabolism leading to increased long-term risk for developing or promoting cancer [3,4,5]. Night shift work has been designated by the International Agency for Cancer Research to be a unique, probable risk factor for developing cancer ostensibly via LAN-induced suppression of melatonin production [8]. Female night shift workers have an increased risk of developing breast [9, 10], colon [11], and endometrial cancer [12], whereas men working in night shifts are at higher risk of prostate cancer as compared with day shift workers [13]
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