Abstract
Glioma relies on glycolysis to obtain energy and sustain its survival under low glucose microenvironment in vivo. The mechanisms on glioma cell glycolysis regulation are still unclear. Signaling mediated by Double-stranded RNA-activated protein kinase (PKR) – like ER kinase (PERK) is one of the important pathways of unfolded protein response (UPR) which is comprehensively activated in cancer cells upon the hypoxic and low glucose stress. Here we show that PERK is significantly activated in human glioma tissues. PERK silencing results in decreased glioma cell viability and ATP/lactate production upon low glucose stress, which is mediated by partially blocked AKT activation and subsequent inhibition of Hexokinase II (HK2)'s mitochondria translocation. More importantly, PERK silenced glioma cells show decreased tumor formation capacity. Our results reveal that PERK activation is involved in glioma glycolysis regulation and may be a potential molecular target for glioma treatment.
Highlights
PERK silence inhibits glioma cell growth under low glucose stress by blockage of p-AKT and subsequent HK2’s mitochondria translocation
Westernblot analysis results showed that unfolded protein response (UPR) related indicators including p-PERK, immunoglobulin heavy chain binding protein (Bip), activating transcription factor 4 (ATF4), and phospho-eukaryotic initiation factor 2a (p-EIF2a) were all highly upregulated in anaplastic astrocytomas (WHO grade III) and glioblatomas (WHO grade IV) compared with nontumor brain tissues, while there was no significant difference of PERK protein level among them (Figure 1 a and Supplementary figure 1)
UPR is extensively activated in cancers, which is an important adaptation for cancer cell survival against microenvironmental stress, such as hypoxia and nutrients deprivation[7,8]
Summary
PERK silence inhibits glioma cell growth under low glucose stress by blockage of p-AKT and subsequent HK2’s mitochondria translocation. PERK silencing results in decreased glioma cell viability and ATP/lactate production upon low glucose stress, which is mediated by partially blocked AKT activation and subsequent inhibition of Hexokinase II (HK2)’s mitochondria translocation. PERK signaling is one of the important downstream pathways of UPR which is comprehensively activated in cancer cells upon the hypoxic and low glucose stress[7,8]. In human glioma, the role of p-AKT on glycolysis is mainly via its regulation on the mitochondria translocation of HK2, which is a key enzyme for glioma energy metabolism and necessary for cell survival under metabolic stress, to mitochondria in glioma cells, resulting in OXPHOX’s inhibition and a large amount of lactate production[5]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
