Abstract
The ability of cancer cells to metastasize represents the most devastating feature of cancer. Currently, there are no specific biomarkers or therapeutic targets that can be used to predict the risk or to treat metastatic cancer. Many recent reports have demonstrated elevated expression of transglutaminase 2 (TG2) in multiple drug-resistant and metastatic cancer cells. TG2 is a multifunctional protein mostly known for catalyzing Ca2+-dependent -acyl transferase reaction to form protein crosslinks. Besides this transamidase activity, many Ca2+-independent and non-enzymatic activities of TG2 have been identified. Both, the enzymatic and non-enzymatic activities of TG2 have been implicated in diverse pathophysiological processes such as wound healing, cell growth, cell survival, extracellular matrix modification, apoptosis, and autophagy. Tumors have been frequently referred to as ‘wounds that never heal’. Based on the observation that TG2 plays an important role in wound healing and inflammation is known to facilitate cancer growth and progression, we discuss the evidence that TG2 can reprogram inflammatory signaling networks that play fundamental roles in cancer progression. TG2-regulated signaling bestows on cancer cells the ability to proliferate, to resist cell death, to invade, to reprogram glucose metabolism and to metastasize, the attributes that are considered important hallmarks of cancer. Therefore, inhibiting TG2 may offer a novel therapeutic approach for managing and treatment of metastatic cancer. Strategies to inhibit TG2-regulated pathways will also be discussed.
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References
Agnihotri N, Kumar S, Mehta K (2013) Tissue transglutaminase as a central mediator in inflammation-induced progression of breast cancer. Breast Cancer Res 15:R202
Ai L et al (2008) The transglutaminase 2 gene (TGM2), a potential molecular marker for chemotherapeutic drug sensitivity, is epigenetically silenced in breast cancer. Carcinogenesis 29:510–518
Antonyak MA et al (2001) Effects of tissue transglutaminase on retinoic acid-induced cellular differentiation and protection against apoptosis. J Biol Chem 276:33582–33587
Antonyak MA, McNeill CJ, Wakshlag JJ, Boehm JE, Cerione RA (2003) Activation of the Ras-ERK pathway inhibits retinoic acid-induced stimulation of tissue transglutaminase expression in NIH3T3 cells. J Biol Chem 278:15859–15866
Belkin AM (2011) Extracellular TG2: emerging functions and regulation. FEBS J 278:4704–4716
Beninati S, Piacentini M (2004) The transglutaminase family: an overview: minireview article. Amino Acids 26:367–372
Block KI et al (2015) Designing a broad-spectrum integrative approach for cancer prevention and treatment. Semin Cancer Biol 35:S276–S304
Boroughs LK, Antonyak MA, Cerione RA (2014) A novel mechanism by which tissue transglutaminase activates signaling events that promote cell survival. J Biol Chem. 289:10115–10125
Brown KD (2013) Transglutaminase 2 and NF-κB: an odd couple that shapes breast cancer phenotype. Breast Cancer Res Treat 137:329–336
Cao L, Shao M, Schilder J, Guise T, Mohammad KS, Matei D (2012) Tissue transglutaminase links TGF-beta, epithelial to mesenchymal transition and a stem cell phenotype in ovarian cancer. Oncogene 31:2521–2523
Chen JS, Mehta K (1999) Tissue transglutaminase: an enzyme with a split personality. Int J Biochem Cell Biol 31:817–836
Cheng ZX et al (2011) Nuclear factor-κB-dependent epithelial to mesenchymal transition induced by HIF-1α activation in pancreatic cancer cells under hypoxic conditions. PLoS One 6:e23752
Chhabra A, Verma A, Mehta K (2009) Tissue transglutaminase promotes or suppresses tumors depending on cell context. Anticancer Res 29:1909–1919
Chua HL et al (2007) NF-kappaB represses E-cadherin expression and enhances epithelial to mesenchymal transition of mammary epithelial cells: potential involvement of ZEB-1 and ZEB-2. Oncogene 26:711–724
Creighton CJ, Chang JC, Rosen JM (2010) Epithelial-mesenchymal transition (EMT) in tumor-initiating cells and its clinical implications in breast cancer. J Mammary Gland Biol Neoplasia 15:253–260
Csomos K, Nemet I, Fésüs L, Balajthy Z (2010) Tissue transglutaminase contributes to the all-trans-retinoic acid-induced differentiation syndrome phenotype in the NB4 model of acute promyelocytic leukemia. Blood 116:3933–3943
Dardik R, Inbal A (2006) Complex formation between tissue transglutaminase II (tTG) and vascular endothelial growth factor receptor 2 (VEGFR-2): proposed mechanism for modulation of endothelial cell response to VEGF. Exp Cell Res 312:2973–2982
Delhase M et al (2012) TANK-binding kinase 1 (TBK1) controls cell survival through PAI-2/serpinB2 and transglutaminase 2. Proc Natl Acad Sci USA 109:177–186
Dyer LM et al (2011) The transglutaminase 2 gene is aberrantly hypermethylated in glioma. J Neurooncol 101:429–440
Eckert RL et al (2014) Transglutaminase regulation of cell function. Physiol Rev 94:383–417
Eckert RL, Fisher ML, Grun D, Adhikary G, Xu W, Kerr C (2015) Transglutaminase is a tumor cell and cancer stem cell survival factor. Mol Carcinog 54:947–958
Erdem S et al (2015) The increased transglutaminase 2 expression levels during initial tumorigenesis predict increased risk of metastasis and decreased disease-free and cancer-specific survivals in renal cell carcinoma. World J Urol 33:1553–1560
Faye C (2010) Transglutaminase-2: a new endostatin partner in the extracellular matrix of endothelial cells. Biochem J 427:467–475
Fesus L (1998) Transglutaminase-catalyzed protein cross-linking in the molecular program of apoptosis and its relationship to neuronal processes. Cell Mol Neurobiol 18:683–694
Fesus L, Piacentini M (2002) Transglutaminase 2: an enigmatic enzyme with diverse functions. Trends Biochem Sci 27:534–539
Fesus L, Szondy Z (2005) Transglutaminase 2 in the balance of cell death and survival. FEBS Lett 579:3297–3302
Fesus L, Tarcsa E (1989) Formation of N epsilon-(gamma-glutamyl)-lysine isodipeptide in Chinese-hamster ovary cells. Biochem J 263:843–848
Fesus L, Thomazy V, Falus A (1987) Induction and activation of tissue transglutaminase during programmed cell death. FEBS Lett 224:104–108
Fischer K et al (2007) Inhibitory effect of tumor cell-derived lactic acid on human T cells. Blood 109:3812–3819
Fisher ML, Keillor JW, Xu W, Eckert RL, Kerr C (2015) Transglutaminase is required for epidermal squamous cell carcinoma stem cell survival. Mol Cancer Res 13:1083–1094
Folkman J (2006) Antiangiogenesis in cancer therapy-endostatin and its mechanisms of action. Exp Cell Res 312:594–607
Gatenby RA, Gillies RJ (2004) Why do cancers have high aerobic glycolysis? Nat Rev Cancer 4:891–899
Gentile V, Thomazy V, Piacentini M, Fesus L, Davies PJ (1992) Expression of tissue transglutaminase in Balb-C 3T3 fibroblasts: effects on cellular morphology and adhesion. J Cell Biol 119:463–474
Grivennikov S et al (2009) IL-6 and Stat3 are required for survival of intestinal epithelial cells and development of colitis-associated cancer. Cancer Cell 15:103–113
Gupta R, Srinivasan R, Nijhawan R, Suri V (2010) Tissue transglutaminase 2 as a biomarker of cervical intraepithelial neoplasia (CIN) and its relationship to p16INK4A and nuclear factor kappaB expression. Virchows Arch 456:45–51
Han AL, Kumar S, Fok JY, Tyagi AK, Mehta K (2014) Tissue transglutaminase expression promotes castration-resistant phenotype and transcriptional repression of androgen receptor. Eur J Cancer 50:1685–1696
Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144:646–674
Hawiger D et al (2001) Dendritic cells induce peripheral T cell unresponsiveness under steady state conditions in vivo. J Exp Med 194:769–779
Hayden MS, Ghosh S (2014) Regulation of NF-κB by TNF family cytokines. Semin Immunol 26:253–266
He Z, Sun ZL (2015) Silencing of TGM2 reverses epithelial to mesenchymal transition and modulates the chemosensitivity of breast cancer to docetaxel. Exp Therp Med 104:1413–1418
Hitomi H, Kojima S, Fesus L (Eds) (2015) Transglutaminases: multiple functional and targets for new drug discovery, Springer
Hsu HS et al (2012) Mesenchymal stem cells enhance lung cancer initiation through activation of IL-6/JAK2/STAT3 pathway. Lung Cancer 75:167–177
Huang S, Ingber DE (2007) A non-genetic basis for cancer progression and metastasis: self-organizing attractions cell regulatory networks. Breast Disease 26:27–54
Huber MA, Beug H, Wirth T (2004a) Epithelial-mesenchymal transition: NF-kappaB takes center stage. Cell Cycle 3:1477–1480
Huber MA et al (2004b) NF-kappaB is essential for epithelial-mesenchymal transition and metastasis in a model of breast cancer progression. J Clin Invest 114:569–581
Hwang JY et al (2008) Clinical and biological significance of tissue transglutaminase (TG2) in ovarian carcinoma. Cancer Res 68:5849–5858
Jeanes A, Gottardi CJ, Yap AS (2008) Cadherins and cancer: how does cadherin dysfunction promote tumor progression? Oncogene 27:6920–6929
Jeong JH et al (2013) Transglutaminase 2 expression predicts progression free survival in non-small cell lung cancer patients treated with epidermal growth factor receptor tyrosine kinase inhibitor. J Korean Med Sci 28:1005–1101
Jones RA (2006) Matrix changes induced by transglutaminase 2 lead to inhibition of angiogenesis and tumor growth. Cell Death Differ 13:1442–1453
Kalluri R (2009) EMT: when epithelial cells decide to become mesenchymal-like cells. J Clin Invest 119:1417–1419
Kanchan K, Fuxreiter M, Fésüs L (2015) Physiological, pathological, and structural implications of non-enzymatic protein-protein interactions of the multifunctional human transglutaminase 2. Cell Mol Life Sci 72:3009–3035
Karin M (2006) Nuclear factor-kappaB in cancer development and progression. Nature 441:431–436
Katsumata N et al (1996) Serum levels of cytokines in patients with untreated primary lung cancer. Clin Cancer Res 2:553–559
Katt WP, Antonyak MA, Cerione RA (2015) Simultaneously targeting tissue transglutaminase and kidney type glutaminase sensitizes cancer cells to acid toxicity and offers new opportunities for therapeutic intervention. Mol Pharm 12:46–55
Kausar T et al (2011) Clinical significance of GPR56, transglutaminase 2, and NF-κB in esophageal squamous cell carcinoma. Cancer Invest 29:42–48
Keillor JW, Apperley KYP, Akbar K (2015) Inhibitors of tissue transglutaminase. Chem Biol 22:1347–1361
Kiberstis PA (2016) Metastasis an evolving story. Science 352:163–174
Kim Y, Eom S (2010) Transglutaminase II interacts with rac1, regulates production of reactive oxygen species, expression of snail, secretion of Th2 cytokines and mediates in vitro and in vivo allergic inflammation. Mol Immunol 47:1010–1022
Kim DS, Park SS, Nam BH, Kim IH, Kim SY (2006) Reversal of drug resistance in breast cancer cells by transglutaminase 2 inhibition and nuclear factor-kappaB inactivation. Cancer Res 66:10936–10943
Kim DS, Park KS, Kim SY (2009) Silencing of TGase 2 sensitizes breast cancer cells to apoptosis by regulation of survival factors. Front Biosci 14:2514–2521
Klöck C, Khosla C (2012) Regulation of the activities of the mammalian transglutaminase family of enzymes. Protein Sci 21:1781–1789
Knupfer H, Preiss R (2007) Significance of interleukin-6 (IL-6) in breast cancer. Breast Cancer Res Treat 102:129–135
Kotiyal S, Bhattacharya S (2014) Breast cancer stem cells, EMT and therapeutic targets. Biochem Biophys Res Commun 453:112–116
Koukourakis MI, Giatromanolaki A, Harris AL, Sivridis E (2006) Comparison of metabolic pathways between cancer cells and stromal cells in colorectal carcinomas: a metabolic survival role for tumor-associated stroma. Cancer Res 66:632–637
Ku BM et al (2014a) Transglutaminase 2 inhibitor abrogates renal cell carcinoma in xenograft models. J Cancer Res Clin Oncol 140:757–767
Ku BM, Lee CH, Lee SH, Kim SY (2014b) Increased expression of transglutaminase 2 drives glycolytic metabolism in renal carcinoma cells. Amino Acids 46:1527–1536
Kumar S, Mehta K (2012) Tissue transglutaminase constitutively activates HIF-1α and nuclear factor-κB via non-canonical pathway. PLoS One 7:e49321
Kumar A et al (2010) Tissue transglutaminase promotes drug resistance and invasion by inducing mesenchymal transition in mammary epithelial cells. PLoS One 5:e13390
Kumar A, Gao H, Xu J, Reuben J, Yu D, Mehta K (2011) Evidence that aberrant expression of tissue transglutaminase promotes stem cell characteristics in mammary epithelial cells. PLoS One 6:e20701
Kumar A, Xu J, Sung B, Kumar S, Yu D, Aggarwal BB, Mehta K (2012) Evidence that GTP-binding domain but not catalytic domain of transglutaminase 2 is essential for epithelial-to-mesenchymal transition in mammary epithelial cells. Breast Cancer Res 14:R4
Kumar S, Donti TR, Agnihotri N, Mehta K (2014) Transglutaminase 2 reprogramming of glucose metabolism in mammary epithelial cells via activation of inflammatory signaling pathways. Int J Cancer 134:2798–2807
Kuo TF, Tatsukawa H, Kojima S (2011) New insights into the functions and localization of nuclear transglutaminase 2. FEBS J 278:4756–4767
Kweon SM et al (2004) Protective role of tissue transglutaminase in the cell death induced by TNF-alpha in SH-SY5Y neuroblastoma cells. J Biochem Mol Biol 37:185–191
Lee AS (2014) Glucose-regulated proteins in cancer: molecular mechanisms and therapeutic potential. Nat Rev Cancer 14:263–276
Lee J et al (2015) Tissue transglutaminase mediated tumor-stroma interaction promotes pancreatic cancer progression. Clin Cancer Res 21:4482–4493
Lee SS, Chen YJ, Tsai CH, Huang FM, Chang YC (2016) Elevated transglutaminase-2 expression mediates fibrosis in areca quid chewing-associated oral submucosal fibrosis via reactive oxygen species generation. Clin Oral Investig 20:1029–1034
Leicht DT et al (2014) TGM2: a cell surface marker in esophageal adenocarcinomas. J Thorac Oncol 9:872–881
Levental KR et al (2009) Matrix crosslinking forces tumor progression by enhancing integrin signaling. Cell 139:891–906
Li B, Antonyak MA, Druso JE, Cheng L, Nikitin AY, Cerione RA (2010) EGF potentiated oncogenesis requires a tissue transglutaminase-dependent signaling pathway leading to Src activation. Proc Natl Acad Sci USA 107:1408–1413
Liu S, Cerione RA, Clardy J (2002) Structural basis for the guanine nucleotide-binding activity of tissue transglutaminase and its regulation of transamidation activity. Proc Natl Acad Sci USA 99:2743–2747
Lorand L, Graham RM (2005) Transglutaminases: crosslinking enzymes with pleiotropic functions. Nat Rev Mol Cell Biol 4:140–156
Mahmood DF, Abderrazak A, El Hadri K, Simmet T, Rouis M (2013) The thioredoxin system as a therapeutic target in human health and disease. Antioxid Redox Signal 19:1266–1303
Malek E, Jagannathan S, Driscoll JJ (2014) Correlation of long non-coding RNA expression with metastasis, drug resistance and clinical outcome in cancer. Oncotarget 5:8027–8038
Mangala LS, Fok JY, Zorrilla-Calancha IR, Verma A, Mehta K (2007) Tissue transglutaminase expression promotes cell attachment, invasion and survival in breast cancer cells. Oncogene 26:2459–2570
Mann AP et al (2006) Overexpression of tissue transglutaminase leads to constitutive activation of nuclear factor-kappaB in cancer cells: delineation of a novel pathway. Cancer Res 66:8788–8795
Mantovani A, Allavena P, Sica A, Balkwill F et al (2012) Cancer-related inflammation. Nature 454:436–444
Matic I et al (2010) Characterization of transglutaminase type II role in dendritic cell differentiation and function. J Leukoc Biol 88:181–188
Mehta K (1994) High levels of transglutaminase expression in doxorubicin-resistant human breast carcinoma cells. Int J Cancer 8:400–406
Mehta K (2005) Mammalian transglutaminases: a family portrait. Prog Exp Tumor Res 38:1–18
Mehta K (2009) Biological and therapeutic significance of tissue transglutaminase in pancreatic cancer. Amino Acids 36:709–716
Mehta K (2016) Tranglutaminase 2 and metastasis—how hot is the link? In: Hitomi K, Kojima S, Fesus L (eds) Transglutaminases: multifunctional modifiers and targets for new drug discovery. Springer, Berlin, pp 215–228
Mehta K, Han A (2011) Tissue transglutaminase (TG2)-induced inflammation in initiation, progression, and pathogenesis of pancreatic cancer. Cancers 3:897–912
Mehta K, Fok J, Miller FR, Koul D, Sahin AA (2004) Prognostic significance of tissue transglutaminase in drug resistant and metastatic breast cancer. Clin Cancer Res 10:8068–8076
Mehta K, Fok JY, Mangala LS (2006) Tissue transglutaminase: from biological glue to cell survival cues. Front Biosci 11:173–185
Mehta K, Kumar A, Kim HI (2010) Transglutaminase 2: a multi-tasking protein in the complex circuitry of inflammation and cancer. Biochem Pharmacol 80:1921–1929
Min B et al (2015) CHIP-mediated degradation of transglutaminase 2 negatively regulates tumor growth and angiogenesis in renal cancer. Oncogene. doi:10.1038/onc.2015.439
Miyoshi N et al (2010) TGM2 is a novel marker for prognosis and therapeutic target in colorectal cancer. Ann Surg Oncol 17:967–972
Murtaugh MP, Arend WP, Davies PJA (1984) Induction of tissue transglutaminase in human peripheral blood monocytes. J Exp Med 159:114–125
Nadalutti C, Viiri KM, Kaukinen K, Mäki M, Lindfors K (2011) Extracellular transglutaminase 2 has a role in cell adhesion, whereas intracellular transglutaminase 2 is involved in regulation of endothelial cell proliferation and apoptosis. Cell Prolif 44:49–58
Nagy L, Thomazy VA, Saydak MM, Stein JP, Davies PJ (1997) The promoter of the mouse tissue transglutaminase gene directs tissue-specific, retinoid-regulated and apoptosis-linked expression. Cell Death Differ 4:534–547
Nakaoka H et al (1994) Gh: a GTP-binding protein with transglutaminase activity and receptor signaling function. Science 264:1593–1596
Nathan C (2002) Points of control in inflammation. Nature 420:846–852
Nunes I, Gleizes PE, Metz CN, Rifkin DB (1997) Latent transforming growth factor-beta binding protein domains involved in activation and transglutaminase-dependent cross-linking of latent transforming growth factor-beta. J Cell Biol 136:1151–1163
Nurminskaya MV, Belkin AM (2012) Cellular functions of tissue transglutaminase. Int Rev Cell Mol Biol 294:1–97
Oh K et al (2011) Transglutaminase 2 facilitates the distant hematogenous metastasis of breast cancer by modulating interleukin-6 in cancer cells. Breast Cancer Res 13:R96
Oliverio S, Amendola A, Rodolfo C, Spinedi A, Piacentini M (1999) Inhibition of “tissue” transglutaminase increases cell survival by preventing apoptosis. J Biol Chem 274:34123–34128
Piacentini M, Melino G, Oliverio S, Piredda L, Biedler JL, Biedler E (1994) Role of tissue transglutaminase in neuroblastoma cells undergoing apoptosis. Prog Clin Biol Res 385:123–129
Piacentini M et al (2005) Type 2 transglutaminase and cell death. Prog Exp Tumor Res 38:58–74
Piacentini M, D’Eletto M, Falasca L, Farrace MG, Rodolfo C (2011) Transglutaminase 2 at the crossroads between cell death and survival. Adv Enzymol Relat Areas Mol Biol 78:197–246
Piacentini M et al (2014) Characterization of distinct sub-cellular location of transglutaminase type II: changes in intracellular distribution in physiological and pathological states. Cell Tissue Res 358:793–805
Pierce A et al (2013) Transglutaminase 2 expression in acute myeloid leukemia: association with adhesion molecule expression and leukemic blast motility. Proteomics 13:2216–2224
Pietsch M, Wodtke R, Pietzsch J, Löser R (2013) Tissue transglutaminase: an emerging target for therapy and imaging. Bioorg Med Chem Lett 23:6528–6543
Pouyssegur J, Dayan F, Mazure NM (2006) Hypoxia signalling in cancer and approaches to enforce tumour regression. Nature 441:437–444
Powis G, Kirkpatrick DL (2007) Thioredoxin signaling as a target for cancer therapy. Curr Opin Pharmacol 7:392–397
Prasad V, Fojo T, Brada M (2016) Precision oncology: origins, optimism, and potential. Lancet Oncol 17:e81–e86
Quan G, Choi JY, Lee DS, Lee SC (2005) TGF-beta1 upregulates transglutaminase 2 and fibronectin in dermal fibroblasts: a possible mechanism for the stabilization of tissue inflammation. Arch Dermatol Res 297:84–90
Ritter SJ, Davies PJ (1998) Identification of a transforming growth factor-beta1/bone morphogenetic protein 4 (TGF-beta1/BMP4) response element within the mouse tissue transglutaminase gene promoter. J Biol Chem 273:12798–12806
Rius J et al (2008) NF-kappaB links innate immunity to the hypoxic response through transcriptional regulation of HIF-1alpha. Nature 453:807–811
Samadi AK et al (2015) A multi-targeted approach to suppress tumor-promoting inflammation. Semin Cancer Biol 35:S151–S184
Sarang Z et al (2005) Tissue transglutaminase (TG2) acting as G protein protects hepatocytes against Fas-mediated cell death in mice. Hepatology 42:578–587
Sarang Z et al (2011) Transglutaminase 2 null macrophages respond to lipopolysaccharide stimulation by elevated proinflammatory cytokine production due to an enhanced alphavbeta3 integrin-induced Src tyrosine kinase signaling. Immunol Lett 138:71–78
Satpathy M et al (2007) Enhanced peritoneal ovarian tumor dissemination by tissue transglutaminase. Cancer Res 67:7194–7202
Shao M et al (2009) Epithelial-to-mesenchymal transition and ovarian tumor progression induced by tissue transglutaminase. Cancer Res 69:9192–9201
Singh A, Settleman J (2010) EMT, cancer stem cells and drug resistance: an emerging axis of evil in the war on cancer. Oncogene 29:4741–4751
Singh G, Zhang J, Ma Y, Cerione RA, Antonyak MA (2016) The different conformational states of tissue transglutaminase have opposing affects on cell viability. J Biol Chem 291:9119–9132
Sullivan NJ et al (2009) Interleukin-6 induces an epithelial-mesenchymal transition phenotype in human breast cancer cells. Oncogene 28:2940–2947
Suto N, Ikura K, Sasaki R (1993) Expression induced by interleukin-6 of tissue-type transglutaminase in human hepatoblastoma HepG2 cells. J Biol Chem 268:7469–7473
Suva ML, Riggi N, Bernstein BE (2013) Epigenetic reprogramming in cancer. Science 339:1567–1570
Takeuchi O, Akira S (2010) Pattern recognition receptors and inflammation. Cell 140:805–820
Tatsukawa H, Furutani Y, Hitomi K, Kojima S (2016) Transglutaminase 2 has opposing role in the regulation of cellular functions as well as cell growth and death. Cell Death Dis 7:e2244
Taylor CT, Pouyssegur J (2007) Oxygen, hypoxia, and stress. Ann N Y Acad Sci 1113:87–94
Thiery JP, Acloque H, Huang RYJ, Nieto MA (2009) Epithelial-mesenchymal transitions development and disease. Cell 139:871–890
Torricelli P, Caraglia M, Abbruzzese A, Beninati S (2012) Gamma-tocopherol inhibits human prostate cancer cell proliferation by up-regulation of transglutaminase 2 and down-regulation of cyclins. Amino Acids 44:45–51
Tóth B et al (2009) Transglutaminase 2 is needed for the formation of an efficient phagocyte portal in macrophages engulfing apoptotic cells. J Immunol 182:2084–2092
Verma A et al (2006) Increased expression of tissue transglutaminase in pancreatic ductal adenocarcinoma and its implications in drug resistance and metastasis. Cancer Res 66:10525–10533
Verma A et al (2008) Tissue transglutaminase regulates FAK/Akt activation by modulating PTEN expression in pancreatic cancer cells. Clin Cancer Res 14:1997–2005
Vicari AP, Caux C, Trinchieri G (2002) Tumour escape from immune surveillance through dendritic cell inactivation. Semin Cancer Biol 12:33–42
Vogelstein B, Papadopoulos N, Velculescu VE, Zhou S, Diaz LA Jr, Kinzler KW (2013) Cancer genome landscapes. Science 339:1546–1558
Wang Z et al (2013) A novel extracellular role for tissue transglutaminase in matrix-bound VEGF-mediated angiogenesis. Cell Death Dis 4:e808
Ward PS, Thompson CB (2012) Metabolic reprogramming: a cancer hallmark even Warburg did not anticipate. Cancer Cell 21:297–308
Wu W, Zhao S (2013) Metabolic changes in cancer: beyond the Warburg effect. Acta Biochim Biophys Sin (Shanghai) 45:18–26
Wu Y, Deng J, Rychahou PG, Qiu S, Evers BM, Zhou BP (2009) Stabilization of snail by NF-kappaB is required for inflammation-induced cell migration and invasion. Cancer Cell 15:416–428
Xu J, Lamouille S, Derynck R (2009) TGF-beta-induced epithelial to mesenchymal transition. Cell Res 19:156–172
Yakubov B et al (2014) Small molecule inhibitors target the tissue transglutaminase and fibronectin interaction. PLoS One 9:e89285
Yamada KM, Even-Ram S (2002) Integrin regulation of growth factor receptors. Nat Cell Biol 4:E75–E76
Yang L, Han S, Sun Y (2014) An IL6-STAT3 loop mediates resistance to PI3K inhibitors by inducing epithelial-mesenchymal transition and cancer stem cell expansion in human breast cancer cells. Biochem Biophys Res Commun 453:582–587
Yoshida GJ (2015) Metabolic reprogramming: the emerging concept and associated therapeutic strategies. J Exp Clin Cancer Res 34:111
Yuan L et al (2007) Transglutaminase 2 inhibitor, KCC009, disrupts fibronectin assembly in the extracellular matrix and sensitizes orthotopic glioblastomas to chemotherapy. Oncogene 26:2563–2573
Zemskov EA, Loukinova E, Mikhailenko I, Coleman RA, Strickland DK, Belkin AM (2009) Regulation of platelet-derived growth factor receptor function by integrin-associated cell surface transglutaminase. J Biol Chem 284:16693–16703
Zemskov EA, Mikhailenko I, Hsia R-C, Zaritskaya L, Belkin AM (2011) Unconventional secretion of tissue transglutaminase involves phospholipid-dependent delivery into recycling endosomes. PLoS One 6:e19414
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The authors wish to thank all the students and trainees from the laboratory whose work is discussed in this review. We regret failure to include many published studies due to space constraints.
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The authors declare that they have no conflict of interest. One of the authors (KM) serves as a Scientific Adviser for Lifecare Innovations (India) and as Board member of MolQ Diagnostics (India) without any compensation.
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Agnihotri, N., Mehta, K. Transglutaminase-2: evolution from pedestrian protein to a promising therapeutic target. Amino Acids 49, 425–439 (2017). https://doi.org/10.1007/s00726-016-2320-2
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DOI: https://doi.org/10.1007/s00726-016-2320-2