Hypoxia, metabolism, and the circadian clock: new links to overcome radiation resistance in high-grade gliomas

Abstract

Radiotherapy is the cornerstone of treatment of high-grade gliomas (HGGs). It eradicates tumor cells by inducing oxidative stress and subsequent DNA damage. Unfortunately, almost all HGGs recur locally within several months secondary to radioresistance with intricate molecular mechanisms. Therefore, unravelling specific underlying mechanisms of radioresistance is critical to elucidating novel strategies to improve the radiosensitivity of tumor cells, and enhance the efficacy of radiotherapy. This review addresses our current understanding of how hypoxia and the hypoxia-inducible factor 1 (HIF-1) signaling pathway have a profound impact on the response of HGGs to radiotherapy. In addition, intriguing links between hypoxic signaling, circadian rhythms and cell metabolism have been recently discovered, which may provide insights into our fundamental understanding of radioresistance. Cellular pathways involved in the hypoxic response, DNA repair and metabolism can fluctuate over 24-h periods due to circadian regulation. These oscillatory patterns may have consequences for tumor radioresistance. Timing radiotherapy for specific times of the day (chronoradiotherapy) could be beneficial in patients with HGGs and will be discussed.

Keywords: Circadian rhythm; High-grade glioma; Hypoxia; Metabolism; Radiotherapy.

Fig. 1

The mechanism of actions whereby the hypoxia inducible factor (HIF-1) regulates glycolysis, lactate pathway and pentose phosphate pathways in radioresistance. ADP, adenosine diphosphate; ATP,adenosine triphosphate; CAIX, carbonic anhydrase 9; G6PD,glucose-6-phosphate dehydrogenase; GLUT, glucose transporters; GSH, glutathione; GSSG, glutathione disulfide; HIF-1, hypoxia inducible factor-1; HK, hexokinase; LDHA, lactate dehydrogenase A; MCT4, monocarboxylate transporter 4; NHE1, Na+/H+ exchanger isoform 1; PDH, pyruvate dehydrogenase; PDK, pyruvate dehydrogenase kinase; ROS, reactive oxygen species

Fig. 2

High-grade gliomas (HGGs) have multiple characteristics that contribute to their aggressive behavior. Increased levels of HIF, glycolysis and radioresistance are common. Circadian dysregulation has also been identified as a recent characteristic contributing to growth, stemness and metabolic changes observed in HGGs

Fig. 3

a The basic mammalian circadian clock loop consists of transcription factors BMAL1 and CLOCK which express PER (PER1, PER2, PER3), CRY (CRY1, CRY2), REV-ERB (NR1D1, NR1D2) and ROR (RORA, RORB, RORC) genes. The PER and CRY proteins accumulate and repress BMAL1/CLOCK activity before being degraded through a mechanism involving casein kinases and the proteasome, which allows BMAL1 and CLOCK activity to resume. In a second loop, the expressed ROR and REV-ERB proteins act to enhance or repress expression of BMAL1 gene. Genes/mRNAs indicated in italics, proteins indicated by colored ovals. b Circadian genes demonstrate cyclical expression over a 24 h period. BMAL1, brain and muscle aryl hydrocarbon receptor nuclear translocator (ARNT)-like 1; CLOCK, circadian locomotor output cycles kaput; PER, period; ROR, RAR-related orphan receptor

Fig. 4

Interactions among hypoxia/HIF, tumor metabolism, circadian rhythm and radioresistance