Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Clinical and Experimental Medicine
Published in: Clinical and Experimental Medicine 3/2017

01-08-2017 | Review Article

IFNs-signaling effects on lung cancer: an up-to-date pathways-specific review

Authors: Vasiliki Galani, Michalis Kastamoulas, Anna Varouktsi, Evangeli Lampri, Antigoni Mitselou, Dimitrios L. Arvanitis

Published in: Clinical and Experimental Medicine | Issue 3/2017

Login to get access

Abstract

IFNs have found important applications in clinical medicine, including the treatment of lung malignancies. The biological effect of the IFN-receptor signaling is regulated essentially by three factors: the expression profile of the IFN itself, the profile of the receptor, and the expression of target genes. IFNs initiate their signaling by binding to specific receptors. The activated IFNs can directly induce gene transcription and/or multiple downstream signaling that both induce diverse cellular responses including the cell cycle arrest and the apoptosis in tumor cells. We provided evidence that IFN-γ enhances the pro cell death effects of Fas/CD95 in human neoplastic alveolar epithelial cell line, A549. We also found that p27 protein plays a pivotal role in the inducing cell death of IFNγ-CH-11-treated A549 cells, since it is involved in the Ras/Raf signaling pathway. This article discusses recent insights into these possible additional functions of IFNs in lung cancer treatment.
Literature
1.
Pestka S, Langer JA, Zoon KC, Samuel CE. Interferons and their actions. Annu Rev Biochem. 1987;56:727–77.CrossRefPubMed
2.
Pfeffer LM, Dinarello CA, Herberman RB, et al. Biological properties of recombinant alpha-interferons: 40th anniversary of the discovery of interferons. Cancer Res. 1998;58(12):2489–99.PubMed
3.
Stark GR, Kerr IM, Williams BR, Silverman RH, Schreiber RD. How cells respond to interferons. Annu Rev Biochem. 1998;67:227–64.CrossRefPubMed
4.
Uddin S, Majchrzak B, Woodson J, et al. Activation of the p38 mitogen-activated protein kinase by type I interferons. J Biol Chem. 1999;274(42):30127–31.CrossRefPubMed
5.
Brierley MM, Fish EN. Review: IFN-alpha/beta receptor interactions to biologic outcomes: understanding the circuitry. J Interferon Cytokine Res. 2002;22(8):835–45.CrossRefPubMed
6.
Parmar S, Platanias LC. Interferons: mechanisms of action and clinical applications. Curr Opin Oncol. 2003;15(6):431–9.CrossRefPubMed
7.
Galani V, Tatsaki E, Bai M, et al. The role of apoptosis in the pathophysiology of Acute Respiratory Distress Syndrome (ARDS): an up-to-date cell-specific review. Pathol Res Pract. 2010;206(3):145–50.CrossRefPubMed
8.
9.
Pestka S. The human interferon alpha species and hybrid proteins. Semin Oncol. 1997;24:S9-4–-17.
10.
Kotenko SV, Gallagher G, Baurin VV, et al. IFN-lambdas mediate antiviral protection through a distinct class II cytokine receptor complex. Nat Immunol. 2003;4(1):69–77.CrossRefPubMed
11.
de Weerd NA, Nguyen T. The interferons and their receptors—distribution and regulation. Immunol Cell Biol. 2002;90(5):483–91.CrossRef
12.
Prokunina-Olsson L, Muchmore B, Tang W, et al. A variant upstream of IFNL3 (IL28B) creating a new interferon gene IFNL4 is associated with impaired clearance of hepatitis C virus. Nat Genet. 2013;45(2):164–71.CrossRefPubMedPubMedCentral
13.
Borden EC, Sen GC, Uze G, et al. Interferons at age 50: past, current and future impact on biomedicine. Nat Rev Drug Discov. 2007;6:975–90.CrossRefPubMed
14.
De Weerd NA, Samarajiwa SA, Hertzog PJ. Type I interferon receptors: biochemistry and biological functions. J Biol Chem. 2007;282:20053–7.CrossRefPubMed
15.
Colamonici OR, Domanski P, Krolewski JJ, et al. Interferon alpha (IFN alpha) signaling in cells expressing the variant form of the type I IFN receptor. J Biol Chem. 1994;2269(8):5660–5.
16.
Novick D, Cohen B, Rubinstein M. The humaninterferon cxlp receptor: characterization and molecular cloning. Cell. 1994;77:391–400.CrossRefPubMed
17.
Domanski P, Witte M, Kellum M, et al. Cloning and expression of a long form of the beta subunit of the interferon alpha beta receptor that is required for signaling. J Biol Chem. 1995;270(37):21606–11.CrossRefPubMed
18.
Bach EA, Aguet M, Schreiber RD. The IFN gamma receptor: a paradigm for cytokine receptor signaling. Annu Rev Immunol. 1997;15:563–91.CrossRefPubMed
19.
Bernabei P, Coccia EM, Rigamonti L, et al. Interferon-gamma receptor 2 expression as the deciding factor in human T, B, and myeloid cell proliferation or death. J Leukoc Biol. 2001;70(6):950–60.PubMed
20.
21.
Sommereyns C, Paul S, Staeheli P, Michiels T. IFN-lambda (IFN-lambda) is expressed in a tissue-dependent fashion and primarily acts on epithelial cells in vivo. PLoS Pathog. 2008;4(3):e1000017.CrossRefPubMedPubMedCentral
22.
Mordstein M, Neugebauer E, Ditt V, et al. Lambda interferon renders epithelial cells of the respiratory and gastrointestinal tracts resistant to viral infections. J Virol. 2010;84(11):5670–7.CrossRefPubMedPubMedCentral
23.
Dickensheets H, Sheikh F, Park O, Gao B, Donnelly RP. Interferon-lambda (IFN-lambda) induces signal transduction and gene expression in human hepatocytes, but not in lymphocytes or monocytes. J Leukoc Biol. 2013;93(3):377–85.CrossRefPubMedPubMedCentral
24.
Uddin S, Platanias LC. Mechanisms of type-I interferon signal transduction. J Biochem Mol Biol. 2004;37(6):635–41.PubMed
25.
Domanski P, Fish E, Nadeau OW, et al. A region of the beta subunit of the interferon alpha receptor different from box 1 interacts with Jakl and is sufficient to activate the Jak-stat pathway and induce an antiviral state. J Biol Chem. 1997;272(42):26388–93.CrossRefPubMed
26.
27.
Platanias LC, Fish EN. Signaling pathways activated by interferons. Exp Hematol. 1999;27:1583–92.CrossRefPubMed
28.
Darnell JE. Studies of IFN-induced transcriptional activation uncover the Jak-Stat pathway. J Interferon Cytokine Res. 1998;18:549–54.CrossRefPubMed
29.
Boehm U, Klamp T, Groot M, Howard JC. Cellular responses to interferon-gamma. Annu Rev Immunol. 1997;15:749–95.CrossRefPubMed
30.
Luszczek W, Cheriyath V, Mekhail TM, Borden EC. Combinations of DNA methyltransferase and histone deacetylase inhibitors induce DNA damage in small cell lung cancer cells: correlation of resistance with IFN-stimulated gene expression. Mol Cancer Ther. 2010;9:2309–21.CrossRefPubMed
31.
32.
Uddin S, Sassano A, Deb DK, et al. Protein kinase C-delta (PKC-delta) is activated by type I interferons and mediates phosphorylation of Stat1 on serine 727. J Biol Chem. 2002;277:14408–16.CrossRefPubMed
33.
Deb DK, Sassano A, Lekmine F, et al. Activation of protein kinase C delta by IFN-gamma. J Immunol. 2003;171:267–73.CrossRefPubMed
34.
Clark AS, West KA, Blumberg PM, Dennis PA. Altered protein kinase C (PKC) isoforms in non-small cell lung cancer cells: PKCdelta promotes cellular survival and chemotherapeutic resistance. Cancer Res. 2003;63(4):780–6.PubMed
35.
Lasfar A, Lewis-Antes A, Smirnov SV, et al. Characterization of the mouse IFN-lambda ligand-receptor system: IFN-lambdas exhibit antitumor activity against B16 melanoma. Cancer Res. 2006;66:4468–77.CrossRefPubMed
36.
Sato A, Ohtsuki M, Hata M, Kobayashi E, Murakami M. Antitumor activity of IFN-lambda in murine tumor models. J Immunol. 2006;176:7686–94.CrossRefPubMed
37.
Ernst M, Jenkins BJ. Acquiring signalling specificity from the cytokine receptor gp130. Trends Genet. 2004;20(1):23–32.CrossRefPubMed
38.
Galani V, Constantopoulos S, Manda-Stachouli C, et al. Additional proteins in BAL fluid of Metsovites environmentally exposed to asbestos: More evidence of “protection” against neoplasia? Chest. 2002;121(1):273–8.CrossRefPubMed
39.
Dauer DJ, Ferraro B, Song L, et al. Stat3 regulates genes common to both wound healing and cancer. Oncogene. 2005;24:3397–408.CrossRefPubMed
40.
Xie TX, Huang FJ, Aldape KD, et al. Activation of stat3 in human melanoma promotes brain metastasis. Cancer Res. 2006;66:3188–96.CrossRefPubMed
41.
Li WC, Ye SL, Sun RX, et al. Inhibition of growth and metastasis of human hepatocellular carcinoma by antisense oligonucleotide targeting signal transducer and activator of transcription 3. Clin Cancer Res. 2006;12:7140–8.CrossRefPubMed
42.
Karamouzis MV, Konstantinopoulos PA, Papavassiliou AG. The role of STATs in lung carcinogenesis: an emerging target for novel therapeutics. J Mol Med. 2007;85:427–36.CrossRefPubMed
43.
Song MM, Shuai K. The suppressor of cytokine signaling (SOCS) 1 and SOCS3 but not SOCS2 proteins inhibit interferon-mediated antiviral and antiproliferative activities. J Biol Chem. 1998;273:35056–62.CrossRefPubMed
44.
Kabir NN, Sun J, Rönnstrand L, Kazi JU. SOCS6 is a selective suppressor of receptor tyrosine kinase signaling. Tumour Biol. 2014;35(11):10581–9.CrossRefPubMed
45.
Lowell CA. Src-family and Syk kinases in activating and inhibitory pathways in innate immune cells: signaling cross talk. Cold Spring Harb Perspect Biol. 2011;3(3):a002352.CrossRefPubMedPubMedCentral
46.
Uddin S, Sher DA, Alsayed Y, et al. Interaction of p59fyn with interferon-activated Jak kinases. Biochem Biophys Res Commun. 1997;235:83–8.CrossRefPubMed
47.
Uddin S, Grumbach IM, Yi T, Colamonici OR, Platanias LC. Interferon alpha activates the tyrosine kinase Lyn in haemopoietic cells. Br J Haematol. 1998;101:446–9.CrossRefPubMed
48.
49.
50.
Carretero J, Shimamura T, Rikova K, et al. Integrative genomic and proteomic analyses identify targets for Lkb1-deficient metastatic lung tumors. Cancer Cell. 2010;17(6):547–59.CrossRefPubMedPubMedCentral
51.
Li Y, Srivastava KK, Platanias LC. Mechanisms of type I interferon signaling in normal and malignant cells. Arch Immunol Ther Exp (Warsz). 2004;52(3):156–63.
52.
White MF, Kahn CR. The insulin signaling system. J Biol Chem. 1994;269(1):1–4.PubMed
53.
Uddin S, Yenush L, Sun XJ, et al. Interferon-alpha engages the insulin receptor substrate-1 to associate with the phosphatidylinositol 3′-kinase. J Biol Chem. 1995;270(27):15938–41.CrossRefPubMed
54.
Platanias LC, Uddin S, Yetter A, Sun XJ, White MF. The type I interferon receptor mediates tyrosine phosphorylation of insulin receptor substrate 2. J Biol Chem. 1996;271(1):278–82.CrossRefPubMed
55.
Kaur S, Katsoulidis E, Platanias LC. Akt and mRNA translation by interferons. Cell Cycle. 2008;7:2112–6.CrossRefPubMed
56.
Chou MM, Blenis J. The 70 kDa S6 kinase: regulation of a kinase with multiple roles in mitogenic signalling. Curr Opin Cell Biol. 1995;7:806–14.CrossRefPubMed
57.
Thyrell L, Hjortsberg L, Arulampalam V, et al. Interferon alpha-induced apoptosis in tumor cells is mediated through the phosphoinositide 3-kinase/mammalian target of rapamycin signaling pathway. J Biol Chem. 2004;279:24152–62.CrossRefPubMed
58.
59.
Platanias LC, Sweet ME. Interferon alpha induces rapid tyrosine phosphorylation of the vav proto-oncogene product in hematopoietic cells. J Biol Chem. 1994;269(5):3143–6.PubMed
60.
Adam L, Bandyopadhyay D, Kumar R. Interferon alpha signaling promotes nucleus-to-cytoplasmic redistribution of p95Vav, and formation of a multisubunit complex involving Vav, Ku80, and Tyk2. Biochem Biophys Res Commun. 2000;267:692–6.CrossRefPubMed
61.
Micouin A, Wietzerbin J, Steunou V, Martyre MC. p95 (vav) associates with the type I interferon (IFN) receptor and contributes to the antiproliferative effect of IFNalpha in megakaryocytic cell lines. Oncogene. 2000;19:387–94.CrossRefPubMed
62.
Uddin S, Lekmine F, Sharma N, et al. The Rac1/p38 mitogen-activated protein kinase pathway is required for interferon alpha-dependent transcriptional activation but not serine phosphorylation of Stat proteins. J Biol Chem. 2000;275:27634–40.PubMed
63.
Gastonguay A, Berg T, Hauser AD, et al. The role of Rac1 in the regulation of NF-κB activity, cell proliferation, and cell migration in non-small cell lung carcinoma. Cancer Biol Ther. 2012;13(8):647–56.CrossRefPubMedPubMedCentral
64.
Stambolic V, Suzuki A, de la Pompa JL, et al. Negative regulation of PKB/Akt-dependent cell survival by the tumor suppressor PTEN. Cell. 1998;95(1):29–39.CrossRefPubMed
65.
Hong TM, Yang PC, Peck K, et al. Profiling the downstream genes of tumor suppressor PTEN in lung cancer cells by complementary DNA microarray. Am J Respir Cell Mol Biol. 2000;23(3):355–63.CrossRefPubMed
66.
Marsit CJ, Zheng S, Aldape K, et al. PTEN expression in non-small-cell lung cancer: evaluating its relation to tumor characteristics, allelic loss, and epigenetic alteration. Hum Pathol. 2005;36(7):768–76.CrossRefPubMed
67.
Chen CL, Chiang TH, Tseng PC, et al. Loss of PTEN causes SHP2 activation, making lung cancer cells unresponsive to IFN-gamma. Biochem Biophys Res Commun. 2015;466(3):578–84.CrossRefPubMed
68.
69.
Ahmad S, Alsayed YM, Druker BJ, Platanias LC. The type I interferon receptor mediates tyrosine phosphorylation of the CrkL adaptor protein. J Biol Chem. 1997;272:29991–4.CrossRefPubMed
70.
Fish EN, Uddin S, Korkmaz M, et al. Activation of a CrkL-stat5 signaling complex by type I interferons. J Biol Chem. 1999;274:571–3.CrossRefPubMed
71.
Miller CT, Chen G, Gharib TG, et al. Increased C-CRK proto-oncogene expression is associated with an aggressive phenotype in lung adenocarcinomas. Oncogene. 2003;22:7950–7.CrossRefPubMed
72.
Platanias LC. The p38 mitogen-activated protein kinase pathway and its role in interferon signaling. Pharmacol Ther. 2003;98:129–42.CrossRefPubMed
73.
Greenberg AK, Basu S, Hu J, et al. Selective p38 activation in human non-small cell lung cancer. Am J Respir Cell Mol Biol. 2002;26:558–64.CrossRefPubMed
74.
Whitmarsh AJ, Davis RJ. Role of mitogen activated protein kinase kinase 4 in cancer. Oncogene. 2007;26:3172–84.CrossRefPubMed
75.
Ventura JJ. p38a MAP kinase is essential in lung stem and progenitor cell proliferation and differentiation. Nat Genet. 2007;39:750–8.CrossRefPubMed
76.
David M, Petricoin EI, Benjamin C, et al. Requirement for MAP kinase (ERK2) activity in interferon alpha- and interferon beta-stimulated gene expression through STAT proteins. Science. 1995;269(5231):1721–3.CrossRefPubMed
77.
Adjei AA. Signal transduction pathway targets for anticancer drug discovery. Curr Pharm Des. 2000;6(4):362–78.CrossRef
78.
Lorusso PM. Phase I and pharmacodynamic study of the oral MEK inhibitor CI-1040 in patients with advanced malignancies. J Clin Oncol. 2005;23:5281–93.CrossRefPubMed
79.
Kastamoulas M, Chondrogiannis G, Kanavaros P, et al. Cytokine effects on cell survival and death of A549 lung carcinoma cells. Cytokine. 2013;61(3):816–25.CrossRefPubMed
80.
Ikeda H, Old LJ, Schreiber RD. The roles of IFN gamma in protection against tumor development and cancer immunoediting. Cytokine Growth Factor Rev. 2002;13(2):95–109.CrossRefPubMed
81.
Hayakawa Y, Takeda K, Yagita H, et al. IFN-gamma-mediated inhibition of tumor angiogenesis by natural killer T-cell ligand, alpha-galactosylceramide. Blood. 2002;100(5):1728–33.PubMed
82.
Liu K, Abrams SI. Coordinate regulation of IFN consensus sequence-binding protein and caspase-1 in the sensitization of human colon carcinoma cells to Fas-mediated apoptosis by IFN-gamma. J Immunol. 2003;170:6329–37.CrossRefPubMed
83.
Vivo C, Lévy F, Pilatte Y, et al. Control of cell cycle progression in human mesothelioma cells treated with gamma interferon. Oncogen. 2001;20:1085–93.CrossRef
84.
Chen B, He L, Savell VH, Jenkins JJ, Parham DM. Inhibition of the interferon-gamma/signal transducers and activators of transcription (STAT) pathway by hypermethylation at a STAT-binding site in the p21WAF1 promoter region. Cancer Res. 2000;60(12):3290–8.PubMed
85.
Galani V, Chondrogiannis G, Kastamoulas M, et al. TNF-alpha, IL1-beta, IL-13 and IFN-gamma effects on the cell death of the A549 lung carcinoma cells. FEBS J. 2009;276(Suppl 1):310.
86.
Fujie H, Tanaka T, Tagawa M, et al. Antitumor activity of type III interferon alone or in combination with type I interferon against human non-small cell lung cancer. Cancer Sci. 2011;102(11):1977–90.CrossRefPubMed
87.
Li W, Huang X, Liu Z, et al. Type III interferon induces apoptosis in human lung cancer cells. Oncol Rep. 2012;28(3):1117–25.PubMed
88.
Tezuka Y, Endo S, Matsui A, et al. Potential anti-tumor effect of IFN-lambda 2 (IL-28A) against human lung cancer cells. Lung Cancer. 2012;78(3):185–92.CrossRefPubMed
89.
Iversen TZ, Andersen MH, Svane IM. The targeting of indoleamine 2,3 dioxygenase-mediated immune escape in cancer. Basic Clin Pharmacol Toxicol. 2015;116(1):19–24.CrossRefPubMed
90.
Jonasch E, Haluska FG. Interferon in oncological practice: review of interferon biology, clinical applications, and toxicities. Oncol. 2001;6(1):34–55.CrossRef
Metadata
Title
IFNs-signaling effects on lung cancer: an up-to-date pathways-specific review
Authors
Vasiliki Galani
Michalis Kastamoulas
Anna Varouktsi
Evangeli Lampri
Antigoni Mitselou
Dimitrios L. Arvanitis
Publication date
01-08-2017
Publisher
Springer International Publishing
Published in
Clinical and Experimental Medicine / Issue 3/2017
Print ISSN: 1591-8890
Electronic ISSN: 1591-9528
DOI
https://doi.org/10.1007/s10238-016-0432-3

Other articles of this Issue 3/2017

Clinical and Experimental Medicine 3/2017 Go to the issue

Original Article

The distribution pattern of ERα expression, ESR1 genetic variation and expression of growth factor receptors: association with breast cancer prognosis in Russian patients treated with adjuvant tamoxifen

Original Article

TLR2 signals via NF-κB to drive IL-15 production in salivary gland epithelial cells derived from patients with primary Sjögren’s syndrome

Original Article

Disruption of the Hedgehog signaling pathway in inflammatory bowel disease fosters chronic intestinal inflammation

Original Article

High-resolution melting combines with Bayes discriminant analysis: a novel hepatitis C virus genotyping method

Letter to the Editor

Vismodegib and risk of cholestatic injury: should we screen candidate patients?

Original Article

Long-term safety of umbilical cord mesenchymal stem cells transplantation for systemic lupus erythematosus: a 6-year follow-up study
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

Read more

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine
Image Credits