Interferon‑α and its effects on cancer cell apoptosis (Review)

Shi, Weiye; Xu, Yong; Fu, Yu; Wang, Yingze

doi:10.3892/ol.2022.13355

Cited by 27 publications

(13 citation statements)

References 86 publications

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“…In cancer cells in general and in MCC cells in particular, type I IFNs can both inhibit their proliferation and induce apoptosis (Willmes et al 2012;Kotredes and Gamero 2013;Shi et al 2022). In line with these reports, treatment of MCPyV-positive WaGa and MKL-1, as well as MCPyVnegative UM-MCC34 MCC cell lines with recombinant IFNα 2a resulted in a dose-dependent inhibition of cell proliferation (Fig.…”

Section: Ifnα Inhibits MCC Cell Proliferation and Induces Apoptosissupporting

confidence: 76%

The HDAC inhibitor domatinostat induces type I interferon α in Merkel cell carcinoma by HES1 repression

Srinivas

Song

Lei

et al. 2023

J Cancer Res Clin Oncol

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Background Class I selective histone deacetylase inhibitors (HDACi) have been previously demonstrated to not only increase major histocompatibility complex class I surface expression in Merkel cell carcinoma (MCC) cells by restoring the antigen processing and presentation machinery, but also exert anti-tumoral effect by inducing apoptosis. Both phenomena could be due to induction of type I interferons (IFN), as has been described for HDACi. However, the mechanism of IFN induction under HDACi is not fully understood because the expression of IFNs is regulated by both activating and inhibitory signaling pathways. Our own preliminary observations suggest that this may be caused by suppression of HES1. Methods The effect of the class I selective HDACi domatinostat and IFNα on cell viability and the apoptosis of MCPyV-positive (WaGa, MKL-1) and -negative (UM-MCC 34) MCC cell lines, as well as, primary fibroblasts were assessed by colorimetric methods or measuring mitochondrial membrane potential and intracellular caspase-3/7, respectively. Next, the impact of domatinostat on IFNA and HES1 mRNA expression was measured by RT-qPCR; intracellular IFNα production was detected by flow cytometry. To confirm that the expression of IFNα induced by HDACi was due to the suppression of HES1, it was silenced by RNA interference and then mRNA expression of IFNA and IFN-stimulated genes was assessed. Results Our studies show that the previously reported reduction in viability of MCC cell lines after inhibition of HDAC by domatinostat is accompanied by an increase in IFNα expression, both of mRNA and at the protein level. We confirmed that treatment of MCC cells with external IFNα inhibited their proliferation and induced apoptosis. Re-analysis of existing single-cell RNA sequencing data indicated that induction of IFNα by domatinostat occurs through repression of HES1, a transcriptional inhibitor of IFNA; this was confirmed by RT-qPCR. Finally, siRNA-mediated silencing of HES1 in the MCC cell line WaGa not only increased mRNA expression of IFNA and IFN-stimulated genes but also decreased cell viability. Conclusion Our results demonstrate that the direct anti-tumor effect of HDACi domatinostat on MCC cells is at least in part mediated via decreased HES1 expression allowing the induction of IFNα, which in turn causes apoptosis.

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Section: Ifnα Inhibits MCC Cell Proliferation and Induces Apoptosissupporting

confidence: 76%

The HDAC inhibitor domatinostat induces type I interferon α in Merkel cell carcinoma by HES1 repression

Srinivas

Song

Lei

et al. 2023

J Cancer Res Clin Oncol

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“…As well, the doubling time for KPC-Luc A and KPC-Luc-4580 cells also corresponded to their levels of resistance to VSV-ΔM51-GFP. It is understood that cancer cells typically downregulate antiviral signaling as these pathways are antiproliferative and pro-apoptotic ( 13 ). Also, in our previous studies, we demonstrated that cells in the G 2 /M cell cycle phase are transcriptionally repressed, leading to a decreased ability of cells to mount antiviral responses ( 33 ).…”

Section: Discussionmentioning

confidence: 99%

“…The pantropism exhibited by VSV is largely due to its use of ubiquitously expressed receptors for attachment and entry into host cells, such as the low-density lipoprotein receptor ( 9 ). The oncoselectivity of most OVs, including VSV, is mainly due to defective or suppressed type I interferon (IFN)-mediated antiviral responses in many cancers ( 10 – 12 ), because most type I IFN responses are antiproliferative, antiangiogenic, and proapoptotic ( 13 ).…”

Section: Introductionmentioning

confidence: 99%

Intertumoral heterogeneity impacts oncolytic vesicular stomatitis virus efficacy in mouse pancreatic cancer cells

Goad,

Nesmelova,

Yohe

et al. 2023

J Virol

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Oncolytic virus (OV) therapy is a promising virus-based approach against various malignancies, including pancreatic ductal adenocarcinoma (PDAC). Our previous studies demonstrated that human PDAC cell lines are highly variable in their permissiveness to OVs. Mouse PDAC cell lines, which are widely used for in vivo examination of the adaptive immune responses during OV and other cancer therapies, have never been examined systematically for the impact of intertumoral heterogeneity (the differences observed between tumors in different patients) on OV virus efficacy. Here, we examined phenotypically and genotypically three commonly used allograftable mouse PDAC cell lines (C57BL6 genetic background): Panc02 (derived from chemically induced PDAC; also known as Pan02), and two cell lines originated from PDACs developed in two different KPC (Kras G12D , Trp53 R172H , and PDX-1-Cre) mouse models. Our study (i) characterized the ability of a widely used attenuated oncolytic vesicular stomatitis virus VSV-ΔM51-GFP to infect, replicate in, and kill mouse PDAC cells; (ii) examined their innate antiviral responses; (iii) compared their permissiveness to a non-attenuated VSV-Mwt-GFP and chemotherapeutic drugs; and (iv) analyzed their karyotype and exome. Mouse PDAC cell lines showed high divergence in their permissiveness to VSV-ΔM51-GFP, which negatively correlated with their abilities to mount innate antiviral responses, while all three cell lines were highly permissive to VSV-Mwt-GFP. No correlation was found between resistance to VSV-ΔM51-GFP and chemotherapy. Also, mouse PDAC cell lines showed high divergence in their karyotype and exome. The exome analysis demonstrated that more VSV-ΔM51-GFP-permissive mouse PDAC cell lines harbor mutations in multiple important antiviral genes, such as TYK2, JAK2, and JAK3. IMPORTANCE Oncolytic virus (OV) therapy is a promising virus-based approach against various malignancies, including pancreatic ductal adenocarcinoma (PDAC). Our previous studies using various human PDAC cell lines demonstrated that they are highly variable in their permissiveness to OVs. In this study, we examined phenotypically and genotypically three commonly used allograftable mouse PDAC cell lines, which are widely used for in vivo examination of the adaptive immune responses during cancer therapies. Mouse PDAC cell lines showed high divergence in their permissiveness to oncolytic vesicular stomatitis virus (VSV), which negatively correlated with their abilities to mount innate antiviral responses. Also, we discovered that more VSV-permissive mouse PDAC cell lines harbor mutations in multiple important antiviral genes, such as TYK2, JAK2, and JAK3. Our study provides essential information about three model mouse PDAC cell lines and proposes a novel platform to study OV-based therapies against different PDACs in immunocompetent mice.

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“…Type I IFN has powerful antitumor and antiviral effects (36). Among them, IFN-α can induce tumor cell apoptosis through the Fas-Fas pathway and plays an important role in tumor immunotherapy (37). IFN-γ is highly expressed in HL tissue cells and tumor HRS cells and has a potential impact on the prognosis of patients (38).…”

Section: Ifnmentioning

confidence: 99%

Cytokines and Lymphoma

Omer¹

2023

Sci Insights

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Currently lymphoma is mainly treated with combination chemotherapy, hematopoietic stem cell transplantation, immunotherapy, and new targeted therapy, but treatment-related drug resistance, recurrence, extranodal and central infiltration, and leukemic transformation are still clinical problems that need to be solved urgently. Studies have shown that cytokines are expressed to varying degrees in lymphoma patients, which are significantly related to the progression of lymphoma, poor prognosis, chemotherapy response, and drug resistance. It has been confirmed that interleukin 6 (IL-6) and IL-10 are highly expressed in all types of lymphoma, and IL-10 is highly expressed in cerebrospinal fluid of central nervous system lymphoma, and both of them indicate poor prognosis. This review discusses the role of cytokines in the development and potential treatment of lymphoma.

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Interferon‑α and its effects on cancer cell apoptosis (Review)

Cited by 27 publications

References 86 publications

The HDAC inhibitor domatinostat induces type I interferon α in Merkel cell carcinoma by HES1 repression

The HDAC inhibitor domatinostat induces type I interferon α in Merkel cell carcinoma by HES1 repression

Intertumoral heterogeneity impacts oncolytic vesicular stomatitis virus efficacy in mouse pancreatic cancer cells

Cytokines and Lymphoma

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