Osteoblast-specific factor 2 reduces glutathione by downregulating PRKRA expression in oral squamous cell carcinoma

Background: Glutathione (GSH) has been increasingly implicated in tumor progression. This study aimed to investigate the role of GSH in oral squamous cell carcinoma (OSCC) and to characterize how its metabolism is modulated.

Methods: Following treatment with osteoblast-specific factor 2 (OSF-2, POSTN), HN6 cells were subjected to RNA sequencing, metabolomics analysis and protein mass spectrometry. Then the levels of GSH, glutathione disulfide (GSSG) and reactive oxygen species (ROS) were measured. Western blot analysis was employed to determine the expression of PRKRA in recombinant human POSTN (rhPOSTN)-treated HN6 cells. Statistical analysis was performed using SPSS 19.0 and P<0.05 was considered to be statistically significant.

Results: Following rhPOSTN treatment, the GSH expression levels were significantly reduced, while the GSSG and ROS levels were significantly increased. Similarly, PRKRA expression was also significantly decreased. Overexpression of PRKRA markedly elevated the GSH levels and reduced the GSSG and ROS levels in OSCC cells. However, this effect was reversed by rhPOSTN. Finally, multiple pathways were implicated in POSTN-induced GSH reduction, of which the first three were apoptotic signaling, Wnt signaling and I-kappaB kinase/NF-kappaB signaling pathways.

Conclusions: Collectively, these findings indicate that POSTN reduced GSH levels through downregulating PRKRA, suggesting that GSH may serve as a potential therapeutic target in OSCC, thereby informing novel strategies for cancer intervention.