SARI inhibits growth and reduces survival of oral squamous cell carcinomas (OSCC) by inducing endoplasmic reticulum stress

Aims: SARI (suppressor of activator protein (AP)-1, regulated by interferon (IFN) was identified as a novel tumor suppressor by applying subtraction hybridization to terminally differentiating human melanoma cells. The antitumor activity of SARI and the correlation between expression and cancer aggression and metastasis has been examined in multiple cancers, but its potential role in oral squamous cell carcinomas (OSCC) has not been explored. Methods: SARI expression was monitored in tumor tissues of OSCC patients by performing immunohistochemistry. Ectopic expression of SARI was achieved using a replication defective adenovirus expressing SARI (Ad. SARI). A nude mouse xenograft model was used to evaluate the in vivo efficacy of SARI. Endoplasmic reticulum (ER) stress was monitored in SARI infected OSCC cells by confocal microscopy. Key finding: In this study, we demonstrate that SARI expression is significantly lower in OSCC tumor tissue as compared to normal adjacent tissue. Ectopic expression of SARI induces cancer-specific cell death in human OSCC cell lines and in a paclitaxel plus cisplatin non-responder OSCC patient-derived (PDC1) cell line. Mechanistically, SARI inhibits zinc finger protein GLI1 expression through induction of endoplasmic reticulum (ER) stress. Using a nude mouse xenograft model, we show that intratumoral injections of Ad.SARI significantly reduce PDC1 tumor burden, whereas treatment with an ER stress inhibitor efficiently rescues tumors from growth inhibition. Significance: Overall, our data provides a link between induction of ER stress and inhibition of the GLI1/ Hedgehog signaling pathway and the tumor suppressive activity of SARI in the context of OSCC.

Automated summary

The study found that SARI expression is significantly lower in oral squamous cell carcinoma tissues compared to normal adjacent tissues. Ectopic expression of SARI induces cancer-specific cell death in OSCC cell lines and inhibits the expression of zinc finger protein GLI1 through induction of endoplasmic reticulum stress. The data provides a link between ER stress induction and inhibition of the GLI1/Hedgehog signaling pathway with the tumor suppressive activity of SARI in OSCC.