Interferon-induced protein with tetratricopeptide repeats (IFIT) genes are prominent interferon-stimulated genes (ISGs). The human IFIT gene family consists of four genes named IFIT1, IFIT2, IFIT3, and IFIT5. The expression of IFIT genes is very low in most cell types, whereas their expression is greatly enhanced by interferon treatment, viral infection, and pathogen-associated molecular patterns (PAMPs). The proteins encoded by IFIT genes have multiple tetratricopeptide repeat (TPR) motifs. IFIT proteins do not have any known enzymatic roles. However, they execute a variety of cellular functions by mediating protein-protein interactions and forming multiprotein complexes with cellular and viral proteins through their multiple TPR motifs. The versatile tertiary structure of TPR motifs in IFIT proteins enables them to be involved in distinct biological functions, including host innate immunity, antiviral immune response, virus-induced translation initiation, replication, double-stranded RNA signaling, and PAMP recognition. The current understanding of the IFIT proteins and their role in cellular signaling mechanisms is limited to the antiviral immune response and innate immunity. However, recent studies on IFIT protein functions and their involvement in various molecular signaling mechanisms have implicated them in cancer progression and metastasis. In this article, we focused on critical molecular, biological and oncogenic functions of human IFIT proteins by reviewing their prognostic significance in health and cancer. Research suggests that IFIT proteins could be novel therapeutic targets for cancer therapy.

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Hybrid molecules are composed of two pharmacophores with different biological activities. Here, we conjugated phthalazine moieties (antiangiogenetic pharmacophore) and bis­(hydroxymethyl)­pyrrole moieties (DNA cross-linking agent) to form a series of bis­(hydroxymethyl)­pyrrolo­[2,1-a]­phthalazine hybrids. These conjugates were cytotoxic to a variety of cancer cell lines by inducing DNA damage, arresting cell cycle progression at the G2/M phase, triggering apoptosis, and inhibiting vascular endothelial growth factor receptor 2 (VEGFR-2) in endothelial cells. Among them, compound 29d encapsulated in a liposomal formulation (e.g., 29dL) significantly suppressed the growth of small-cell lung cancer cell (H526) xenografts in mice. Based on immunohistochemical staining, the tumor xenografts in mice treated with 29dL showed time-dependent decreases in the intensity of CD31, a marker of blood vessels, whereas the intensity of γ-H2AX, a marker of DNA damage, increased. The present data revealed that the conjugation of antiangiogenic and DNA-damaging agents can generate potential hybrid agents for cancer treatment.

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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.

Small cell lung cancer (SCLC) is an aggressive type of lung cancer and accounts for 10% to 15% of all lung cancer cases. The malignancy has a greater tendency to be widely disseminated by the time of diagnosis as well as to develop early resistance to conventional treatments, a cure is difficult to achieve. The current standard therapy for SCLC treatment, either with monotherapy (platinum based drugs) or combination therapy (e.g., cisplatin with irinotecan or topotecan), was shown to cause serious side effects and inevitably evoke drug resistance in a short time period. We have recently synthesized a series of novel bis(hydroxymethyl)indolizino[8,7-b]indole hybrids by fusing β-carboline and bis(hydroxymethyl)pyrrole moieties for antitumor evaluation. These hybrid molecules displayed diverse mechanisms of action involving topoisomerase II (Topo II) inhibition and induction of DNA cross-linking. Our results also showed that they significantly inhibited the cell growth of various human tumor cell lines. Of the tested tumor cell lines, the SCLC cells (H526 and H211) were the most susceptible to compounds BO-2239 and BO-2329. These hybrids induced cell cycle arrest at the G2/M phase and triggered tumor cell apoptotic death. Intriguingly, the substituent at N11 (H or Me) played a critical role in modulating Topo II inhibition and DNA cross-linking. Compared to the compounds with N11-Me group, derivatives having N11-H group profoundly increased Topo II inhibition activity but reduced DNA cross-linking activity. Among these hybrids, BO-2239 (with N11-H) was as potent as irinotecan, but more effective than cisplatin, in nude mice bearing SCLC H526 xenografts. Accordingly, hybrid BO-2239 may be further developed as a potential agent for the treatment of SCLC. Citation Format: Sue-Ming Chang, Ming-Hsi Wu, Hima Bindu Pidugu, Tsann-Long Su, Te-Chang Lee. Novel indolizino[8,7-b]indole hybrids with potent activity against small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5126. doi:10.1158/1538-7445.AM2017-5126

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

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