Abstract B034: IFIT1 and IFIT3 function as Hsp90 co-chaperones to modulate the drug response in human oral squamous cell carcinoma

Abstract

Abstract Oral squamous cell carcinoma (OSCC) is one of the most common malignant cancers with poor clinical outcome in the patients treated with chemotherapeutics. To improve the potential treatment approaches for OSCC patients, it is an urgent need to understand the molecular signaling mechanism involved in OSCC drug resistance. The failure of chemotherapy or targeted therapy is due to the development of drug resistance to anti-cancer drugs by various intrinsic cellular mechanisms. In the tumor microenvironment, cancer cells are exposed to many cellular components such as growth factors, extracellular matrix, and cytokines, etc. Interferons are pleiotropic cytokines promote cancer cells to acquire malignant phenotype and drug resistance through transcriptional induction of interferon-stimulated genes (ISGs). The human interferon-induced protein with tetratricopeptide repeats (IFIT) genes: IFIT1, IFIT2, IFIT3, and IFIT5 are well-known ISGs with multiple tetratricopeptide motifs that mediate protein-protein interactions. We have previously shown that high IFIT1 or IFIT3 expression promoted OSCC invasion and metastasis by EGFR signaling via enhancing EGFR endocytic recycling. However, the clinical significance of IFIT1 and IFIT3 in OSCC drug resistance remains unexplored. In the present study, we found that overexpression of IFIT1 or IFIT3 proteins in OSCC cells notably increased the resistance to DNA damaging agents including cisplatin, carboplatin, and oxaliplatin. In addition, xenograft tumors derived from IFIT1 or IFIT3-overexpressed cells showed resistance to cisplatin compared to controls. Intriguingly, our protein-protein interaction studies have revealed that IFIT1 and IFIT3 interacted with molecular chaperone Hsp90. Furthermore, ectopic expression of IFIT1 or IFIT3 induced C-terminal phosphorylation of Hsp90-α and subsequently activated of its client proteins, such as EGFR, AKT, p38, and SAPK/JNK in OSCC cells. Also, IFIT1 or IFIT3-overexpressed cells showed resistance to Hsp90 inhibitors such as geldanamycin and ganetespib. Suppression of Hsp90 activation by ganetespib resulted in decreased activation of downstream client proteins in IFIT1- or IFIT3-overexpressing cells. Moreover, IFIT1- or IFIT3-overexpressing cells showed enhanced expression of cancer stem cell marker c-Met compared to vector control cells. These results suggested a novel role of IFIT1 and IFIT3 in activating Hsp90 and several downstream signaling regulators which are critical for drug resistance in OSCC cells. Collectively, our results indicate that IFIT1 and IFIT3 possibly act as co-chaperones and serve as potentially important therapeutic targets for OSCC treatment in the future. Citation Format: Vijaya Pidugu, Hima Pidugu, Yu-Hsiang Teng, Te-Chang Lee. IFIT1 and IFIT3 function as Hsp90 co-chaperones to modulate the drug response in human oral squamous cell carcinoma [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr B034. doi:10.1158/1535-7163.TARG-19-B034