Circadian regulation of astrocytic adenosine kinase in the irradiated and cancer brain

ABSTRACT Cranial radiotherapy (CRT) for CNS cancers leads to debilitating cognitive decline that is particularly concerning for pediatric and grade II/III brain cancer survivors. CRT triggers inflammation and astrogliosis, leading to cognitive dysfunction. Astrocytes control the availability of adenosine (ADO), a neuroprotectant and modulator

of cognition, via adenosine kinase (ADK), which gets elevated post-CRT. ADO exerts neuroprotection by activation of adenosine receptors (A1R) that play important roles in synaptic plasticity and cognition. ADK, by controlling synaptic ADO levels and A1R activation, fine-tunes the sleep-wake cycle which is dysregulated

following CRT. Sleep-wake disruption and cognitive impairments are among the most common symptoms in brain cancer patients undergoing CRT, but mechanisms underlying its occurrence are not fully understood. The circadian clock is centrally mediated by the suprachiasmatic nucleus (SCN), and functions at the cellular level

via an intricate transcription-translation feedback loop consisting of the transcription factors, Aryl ReceptorNuclear Translocator Like (ARNTL, also known asBMAL1) and Circadian Hydrocarbon Locomotor Output Cycles Kaput (CLOCK) proteins. Though the role of these proteins in cancer is complex, we have shown that BMAL1

suppresses the growth of hepatocellular carcinoma via interacting with tumor suppressor genes. Using the mouse model of CRT and astrocytoma, our preliminary observations indicate that: i) BMAL1 binds to target sites in the Adk gene in a circadian manner and, ii) CRT reduces BMAL1 in the normal and cancer-bearing mouse

SCN. We hypothesize that CRT disrupts BMAL1-mediated sleep regulation in both normal and cancerous tissue, in a cell type-specific (astrocytes) and ADK-dependent manner. Using a genetic approach, astrocyte selective, double knockout of Clock and Bmal1 in vitro and in vivo, this application will determine the impact of BMAL1 and

CLOCK on the Adk gene and brain region-specific expression of circadian proteins in mice brains with or without astrocytoma receiving cranial radiotherapy. This study will reveal key mechanistic information regarding sleep/wake (dys)regulation following CRT for brain cancers.