title: Light at night activates IGF-1R/PDK1 signaling and accelerates tumor growth in human breast cancer xenografts.
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.
authors.affiliation: Bassett Research Institute and Department of Internal Medicine, Bassett Healthcare Network, Cooperstown, New York, USA.
authors.forename: Jinghai
authors.initials: J
authors.lastname: Wu
authors.forename: Robert T
authors.initials: RT
authors.lastname: Dauchy
authors.forename: Paul C
authors.initials: PC
authors.lastname: Tirrell
authors.forename: Steven S
authors.initials: SS
authors.lastname: Wu
authors.forename: Darin T
authors.initials: DT
authors.lastname: Lynch
authors.forename: Potjana
authors.initials: P
authors.lastname: Jitawatanarat
authors.forename: Christine M
authors.initials: CM
authors.lastname: Burrington
authors.forename: Erin M
authors.initials: EM
authors.lastname: Dauchy
authors.forename: David E
authors.initials: DE
authors.lastname: Blask
authors.forename: Michael W
authors.initials: MW
authors.lastname: Greene
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology*; D048708:Cell Growth Processes / Q000502:physiology / Q000528:radiation effects; D045744:Cell Line, Tumor; D002940:Circadian Rhythm / Q000502:physiology*; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008027:Light; D018809:Proliferating Cell Nuclear Antigen / Q000096:biosynthesis; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D051381:Rats; D011923:Rats, Nude; D017526:Receptor, IGF Type 1 / Q000378:metabolism*; D015398:Signal Transduction / Q000528:radiation effects; D014183:Transplantation, Heterologous
chemical_list: C000631429:PDK1 protein, human; C000631434:Pdk1 protein, rat; D018809:Proliferating Cell Nuclear Antigen; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1; D017346:Protein Serine-Threonine Kinases