Abstract
Simple SummaryIFIT2 depletion is associated with increased epithelial-mesenchymal transition and metastasis. The main aim of our study was to understand the link between drug resistance and IFIT2 depletion. In this study, we confirmed resistance to multiple common therapeutic drugs, particularly 5-FU, which showed especially high resistance in IFIT2-depleted cells. Interestingly, combination of SAHA and 5-FU overcame 5-FU resistance in IFIT2-depleted cells. Hence, our findings suggest that IFIT2 expression may be used as a biomarker to decide whether to undergo 5-FU treatment, but also the SAHA and 5-FU combination may be a potential new treatment regimen to augment 5-FU therapy in patients with thymidylate synthase-mediated drug-resistant oral squamous cell carcinoma.Interferon-induced protein with tetratricopeptide repeats 2 (IFIT2) is a member of the interferon-stimulated gene family that contains tetratricopeptide repeats (TPRs), which mediate protein–protein interactions in various biological systems. We previously showed the depletion of IFIT2 enhanced cell migration and metastatic activity in oral squamous cell carcinoma (OSCC) cells via the activation of atypical PKC signaling. In this study, we found that IFIT2-knockdown cells displayed higher resistance to 5-fluorouracil (5-FU) than control cells. The comet assay and annexin V analysis showed decreased DNA damage and cell death in IFIT2-knockdown cells compared to control cells treated with 5-FU. Cell cycle progression was also perturbed by 5-FU treatment, with the accumulation of IFIT2-depleted cells in S phase in a time-dependent manner. We further observed the overexpression of thymidylate synthase (TS) and thymidine kinase (TK) in IFIT2-knockdown cells. Inhibition of TS alone or double inhibition of TS and TK1 using the siRNA technique increased susceptibility to 5-FU in IFIT2-knockdown cells. We further identified that suberanilohydroxamic acid (SAHA) treatment decreased the expression of TS in IFIT2-knockdown cells and demonstrated that pretreatment with SAHA sensitized IFIT2-knockdown cells to 5-FU in vitro and in vivo. In conclusion, IFIT2 knockdown enhances TS expression, which mediates 5-FU resistance, and SAHA pretreatment suppresses TS expression and hence sensitizes cells to 5-FU. SAHA will be an effective strategy for the treatment of OSCC patients with 5-FU resistance.
Highlights
Interferon-induced protein with tetratricopeptide repeats (IFITs) are members of the IFN-stimulated gene family and are considered highly responsive to IFNs, viruses and pathogen-associated molecularCancers 2020, 12, 3527; doi:10.3390/cancers12123527 www.mdpi.com/journal/cancersCancers 2020, 12, 3527 patterns [1,2]
We showed that Interferon-induced protein with tetratricopeptide repeats 2 (IFIT2) depletion activated atypical protein kinase signaling, increased migration, invasion, and metastasis and regulated TNF-α secretion, leading to angiogenesis and chemoresistance in oral squamous cell carcinoma (OSCC) [17,18]
We found that the histone deacetylases (HDACs) inhibitor suberanilohydroxamic acid (SAHA) attenuated 5-FU resistance in IFIT2-depleted cells
Summary
Interferon-induced protein with tetratricopeptide repeats (IFITs) are members of the IFN-stimulated gene family and are considered highly responsive to IFNs, viruses and pathogen-associated molecularCancers 2020, 12, 3527; doi:10.3390/cancers12123527 www.mdpi.com/journal/cancersCancers 2020, 12, 3527 patterns [1,2]. Interferon-induced protein with tetratricopeptide repeats (IFITs) are members of the IFN-stimulated gene family and are considered highly responsive to IFNs, viruses and pathogen-associated molecular. The human IFIT family is encoded by four evolutionarily conserved genes, IFIT1, IFIT2, IFIT3 and IFIT5, which are clustered on chromosome 10 [3]. The IFIT family displays broad-spectrum antiviral functions [4]. Emerging evidence has shown that IFIT proteins participate in diverse signaling mechanisms involved in cancer progression and metastasis [5]. IFIT1, IFIT3 and IFIT5 proteins play significant roles in malignant progression [2,6,7], whereas numerous reports have shown that decreased IFIT2 expression is associated with tumor progression and poor survival of patients with different cancers [8,9]. Overexpression of the IFIT2 protein was found to inhibit proliferation or promote apoptosis in a variety of cancer cell lines [10,11,12,13,14,15]
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