Abstract 2098: IFIT1 and IFIT3 modulate the drug response in human oral squamous cell carcinoma through interaction and activation of Hsp90

Abstract

Abstract Interferon-induced protein with tetratricopeptide repeats (IFITs) family, well-known interferon-stimulated genes, have multiple tetratricopeptide repeats with helix-turn-helix structural motifs that mediate a variety of protein-protein interactions. Four IFIT genes have been identified in humans: IFIT1, IFIT2, IFIT3, and IFIT5. While the importance of IFIT1 and IFIT3 in the prognosis of cancer has been reported, the molecular basis of IFIT1 and IFIT3 in cancer progression remains unexplored. We have previously shown that high IFIT1 and IFIT3 expression associated with advanced T-stage, lymph node metastasis, perineural invasion, lymphovascular invasion, extranodal extension, and poor overall survival rate in oral squamous cell carcinoma (OSCC) patients. Also, we have demonstrated that high IFIT1 or IFIT3 expression promoted OSCC invasion and metastasis by EGFR signaling via enhancing EGFR endocytic recycling. Intriguingly, our recent studies have revealed the involvement of IFIT1 and IFIT3 in the resistance to chemotherapeutic agents in OSCC cells. The failure of chemotherapy or targeted therapy was often associated with the intrinsic or acquired drug resistance in cancer cells. In the present study, we intended to explore the biological role of IFIT1 and IFIT3 on drug resistance in OSCC cells. Our results showed that ectopic expression of IFIT1 or IFIT3 proteins in OSCC cells significantly increased the resistance to various therapeutic drugs such as cisplatin, carboplatin, 5-FU, and doxorubicin. Whereas, silencing of IFIT1 and IFIT3 by shRNA enhanced the sensitivity to these drugs. We further demonstrated that enhanced expression of IFIT1 and IFIT3 significantly increased the levels of C-terminal phosphorylation of Hsp90 and activation of its client proteins, such as EGFR, AKT, p38, and SAPK/JNK. Using mass spectrophotometric, immunoprecipitation and immunofluorescence analyses, we identified the interactions of IFIT1 and IFIT3 with Hsp90. Suppression of Hsp90 by a specific inhibitor resulted in decreased activation of its downstream targets in IFIT1- or IFIT3-overexpressing cells. These results suggested a novel mechanism of IFIT1 and IFIT3 in activating Hsp90 and several downstream signaling regulators which are crucial for OSCC tumor progression and drug resistance. Thus, IFIT1 and IFIT3 may act as co-chaperones and serve as potentially important prognostic biomarkers for OSCC progression. Citation Format: Vijaya Kumar Pidugu, Meei-Maan wu, Hima Bindu Pidugu, Te-Chang Lee. IFIT1 and IFIT3 modulate the drug response in human oral squamous cell carcinoma through interaction and activation of Hsp90 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2098.