C1QBP regulates apoptosis of renal cell carcinoma via modulating xanthine dehydrogenase (XDH) mediated ROS generation

Abstract

Background Complement component 1 Q subcomponent binding protein (C1QBP) is a multifunctional protein and plays a vital role in the progression and metabolism of cancer. Our previous study has revealed that the low expression of C1QBP in renal cell carcinoma (RCC) and knockdown of C1QBP promotes the adhesion and invasion of RCC cells. However, its functions in the metabolism, oxidative stress and apoptosis of RCC cells have not yet been explored. Methods Metabolomics assay was applied to investigate the role of C1QBP in RCC metabolism. C1QBP knockdown and overexpression cells were established via lentiviral infection and subjected to apoptosis and ROS assay in vitro. RNA stability assay and pre-mRNA detection were applied to characterize the mechanism of C1QBP regulating XDH transcription. In vivo, orthotopic tumor xenografts assay was performed to investigate the role of C1QBP progression. Results Metabolomics investigations revealed that C1QBP dramatically diminished the hypoxanthine content in RCC cells. C1QBP promoted the mRNA and protein expression of hypoxanthine catabolic enzyme xanthine dehydrogenase (XDH). Meanwhile, C1QBP regulated the expression of XDH gene at the pre-transcriptional level by regulating XDH transcriptional stimulators IL-6, TNF-α and IFN-γ. Moreover, the expression of C1QBP and XDH was lower in RCC tumors compared with the para-tumor normal tissues, and their down-regulation was associated with higher levels of Fuhrman grade. In RCC cells, C1QBP significantly increased produces reactive oxygen species (ROS) levels, apoptosis, and the expression of apoptotic proteins cleaved caspase-3 and bax/bcl2 via regulating XDH.Conclusions C1QBP promotes the catabolism of hypoxanthine and elevates the apoptosis of RCC cells by modulating XDH-mediated ROS generation.

Increased ENT2 Expression and Its Association With Altered Purine Metabolism in Different Stages of Colorectal Cancer Cell Lines

“…Consistent with our ndings, several studies reported that XO activity was decreased in a number of cancers, such as colon cancer [39], kidney and bladder [40]. In addition, low XO expression was correlated with more aggressive cancers [41], indicating that XO plays an important role in cancer progression and may become a risk factor [42]. The decrease in XO activity might provide an advantage to the cancer cells by reducing the generation of ROS, which may induce the apoptosis pathway and cell death.…”

“…During salvage purine metabolism, hypoxanthine can be either recycled to inosine monophosphate (IMP) by HPRT or synthesized by deamination of adenosine by adenosine deaminase (ADA) to produce inosine; inosine will be converted to hypoxanthine by purine nucleoside phosphorylase (PNP) [33]. Later, during the purine catabolism pathway, hypoxanthine will be converted to xanthine then to uric acid by xanthine oxidase.Reactive oxygen species (ROS) will be produced as a by-product of the catabolism pathway [42]. The increasing level of intracellular ROS is postulated to induce apoptosis and cancer cell death.…”