Research Center of Thalassemia and Hemoglobinopathy, Jondishapoor University of Medical Science, Ahwaz, Iran.
Research Center of Thalassemia and Hemoglobinopathy, Jondishapoor University of Medical Science, Ahwaz, Iran.
Signal Transducer and Activator of Record (Detail) can assume a part in the development or hindrance of malignant growth by directing cytokine-subordinate resistance and aggravation. Details comprise a gathering of record factors including seven individuals that were recognized around quite a while back when the interferon quality pathway was inspected. Details connect the receptor feeling with quality record and send a sign to the comparing quality. The essential job of this family of sign transducers in cell development in both ordinary and threatening circumstances makes them fascinating focuses for malignant growth treatment methodologies. STAT3 in this family goes about as an oncogene that assumes a part in human diseases. As a significant flagging protein, STAT3 might be engaged with tumorigenesis, angiogenesis, and disease cell metastasis as well as chemoresistance. Consequently, STAT3 restraint is viewed as a therapy strategy on the grounds that its hindrance could be a possibility for disease treatment without influencing ordinary cells. Different individuals from this gathering of record factors are likewise engaged with neoplasia, and the restraint or potentially enlistment of its capability might assume part in controlling disease cell development or setting off separation and development enlistment processes. This paper means to audit the future of focusing on Details family in malignant growth treatment techniques.
Keywords: Cancer, Signaling pathway, Treatment, Inhibition, STAT, STAT3,
Mammalian cells include a series of transcription factors known as Signal Transducer and Activator of Transcription (STAT). Nearly 20 years ago, researchers studying the signalling pathway(s) connected to the interferon gene discovered that STAT are engaged in downstream signalling of several growth factors and cytokine receptors [1,2]. Members of this family are involved in cytokine responses as well as cell proliferation, apoptosis, pro-inflammatory, and antiproliferative actions; hence, dysregulation of this pathway may contribute to neoplasia. Theoretically, research on the possible stimulation or inhibition of one or more of these protein types could be used to develop targeted treatment approaches. STAT build a link between nuclear gene transcription and cytokine receptor activation.
STAT are proteins that are engaged in a wide range of cellular processes and can be found in both healthy and disease- and cancer-related cells [3]. Seven members of the STAT family have been identified, including STAT1 through STAT6 and STAT5. The latter comes in two varieties, STAT5a and STAT5b. The primary variations among these individuals are determined by their functions, peptide sizes (between 750 and 850 amino acids), and structural characteristics [4].
The genes that make up STAT molecules come from three chromosomes, specifically chromosomes 2, 12, and 17. Chromosome 2 codes for STATs 1 and 4, Chromosome 12 codes for STATs 2 and 6, Chromosome 17 (17q21.2) codes for STAT3, and Chromosome 17 (chr17) codes for STAT5 (17q11.2) [5]. Similar STAT proteins have a six conserved domain structure from N to C terminals [6].The expression of nuclear genes and protein-protein interactions are both influenced by the N-terminal domain (ND). This portion stabilises the DNA link by forming tetramers from its four hydrophobic coiled alpha helices that participate in hetero- and homo-dimers.for tying the DBD area to the SH2 region. The recipient's phosphotyrosine region and the SH2 region work together to communicate amongst other areas. With its tyrosine and serine-rich sections, the Transcriptional Activation Domain (TAD), a component of the C-terminal, facilitates the phosphorylation of STATs [3,7]. DNA binding, chromatin remodelling, and the regulation of certain gene expression can all be influenced by the structure of STAT dimer combinations [8]. The amino-terminal regions of STAT 1-4 include a repeating heptad leucine motif, and STAT proteins have a range of carboxyterminal architectures [9].
Like other Detail relatives, STAT1 can decipher and move signals from the cytoplasmic layer and cytoplasm to the core. STAT1 can decipher and communicate the message of different ligands like IL-21, IL-27, and IL-35. Then again, it is profoundly enacted by any IFN type and makes homodimers [10].Enactment of STAT1 happens in two distinct ways by phosphorylation in two locales. The main way, to be specific tyrosine 705 (Y705) phosphorylation, prompts the enactment of message and its move to the core. Be that as it may, the subsequent condition happening later
feeling of IFNs in light of cell stress, to be specific the Ser727,phosphorylates STAT1 and can play various jobs, including cell passing, development, and separation [11].STAT1 goes about as a growth silencer, and its intrinsic ransformations can cause genetic issues, including an assortment of immune system diseases.STAT1 changes were first seen in quite a while with parasitic furthermore, bacterial infections, for example, mycobacteria [12].STAT1 can be associated with cell development restraint by smothering CDK inhibitor and p21Cip1 inhibitor qualities [3].
STAT2 enactment is likewise a component of IFN flags and can partake in STAT1/STAT2 heterodimer, which improves the articulation of qualities related with IFN improvements.Concentrates on STAT1 what's more, STAT2 qualities of thump down mice have shown that these mice were not receptive to IFN and that they had a high powerlessness to contamination. By the by, the job of STAT2 protein in disease has not been concentrated without help from anyone else; rather, it has been oncentrated other than STAT4 that assumes a part in Th1anti-growth safe reaction [3].IL-12 actuates STAT4 by restricting to its particular receptor on CD4+Th-cells by phosphorylating tyrosine 693 and serine 721 in STAT4, moving to the core and restricting to DNA. STAT4 works on the capability of provocative cytokines like IFN-γ inmyeloid cells, actuated monocytes, macrophages, and dendritic cells.
Likewise, it can play an antiviral, mitigating, and fibrinogenesis job [13,14].STAT5 is phosphorylated by Janus kinases at Tyr694 and Tyr699 furthermore, dimerized by the SH2 space [15]. This dimer controls the capability of IFN-γ by moving to the core and restricting to DNA [16].STAT6 tweaks the resistant reactions and hypersensitive irritation through guideline of IL-4 and IL-13 quality articulation in various cells [14,17].
STAT3 is one of the main flagging proteins included in the transmission of messages from the film to the core. Dissimilar to STAT1, STAT3 has demonstrated to cause disease. This protein is essentially actuated in 25% to 100 percent of malignancies. It adds to the departure of disease cells from the safe framework and their protection from chemotherapy and radiotherapy. Subsequently, STAT3 restraint is viewed as a treatment target [18].A review has shown that extreme STAT3 flagging plays an
significant job in chemotherapy opposition and that the hindrance of dynamic STAT3 flagging causes drug opposition in cancer cells that become delicate to harmful specialists [19].Under typical physiological circumstances, the situation with STAT3 phosphorylation in the cell relies upon the reaction to extracellular improvements, so that signal force and term control that the reaction. Neurotic circumstances brought about by irregularities in flagging pathways as well as different factors, for example, unnecessary emission of development chemicals and cytokines can prompt further phosphorylation of STAT3 [20].
STAT3 flagging fountain gives numerous open doors to controlling its action in light of the fact that each move toward the course of enactment could act as an objective. In this manner, ruling the actuation pathway could add to control of treatment reaction [3].To initiate STAT3, the ligand ties to the receptor and causes phosphorylation at Tyr705. It causes primary changes in the tail area and afterward ties to phosphotyrosine locale of SH2 from the partner Detail and there by structures a dimer. By restricting to the advertiser area on DNA, this dimer causes quality articulation, which advances the improvement of cell cycle and cell homeostasis.STAT3 has no enzymatic movement and can't be hindered in this way. All things considered, it generally communicates with protein and ties to DNA, and this specific element prepares it for this cycle through little meddling atoms and inhibitors[3,21].
Transformed genes known as oncogenes alter the phenotypic and cellular structure of cells. Oncogenes were initially identified in the viral genome, and it was later shown that they are active in a variety of cell types. As an oncogene, STAT3 causes a variety of solid and haematological tumours when it becomes overactive in different types of cancer. With its excessive activity, this gene promotes cell growth and proliferation while blocking apoptosis, which causes metastasis and angiogenesis [22].
STAT3 is over communicated in numerous human malignant growths and plays a key job in tumorigenesis, angiogenesis, and disease cell metastasis. Hindrance or control of STAT3-related quality articulation have some control over the movement of disease cells with least secondary effects on sound cells [23]. Malignant growth cells in which STAT3 is over communicated influence the safe cells and restrain their exercises and lead to proceeded with development of bmalignant growth cells [24].
Angiogenesis happens because of the actuation of Vascular Endothelial Development Element (VEGF) in disease cells that causes cancer development and metastasis.STAT3 is a direct transcriptional activator of VEGF that animates angiogenesis [25-27].
Malignant growth metastasis happens after transmission of disease cells to tissues around the growth and afterward by angiogenesis and entrance into blood dissemination prompting their exchange to additional far off tissues.Protein tyrosine kinases, oncogenes, and infections can initiate STAT3 to change dangerous cells [28]. Cell setting influences STAT3 flagging, which controls growth development and concealment. Cancer size and the pace of metastasis are conversely connected with STAT3 articulation, decreased high-impact glycolysis and energy digestion in disease cells through concealment of cancer articulation through expanding STAT3 articulation [29]. Sosonkina N et al. [30] showed that the thyroid organ over communicates STAT3 for typical function.STAT3 phosphorylation at
Tyr705 of thyroid epithelium happens in both the cytoplasm and core.STAT3 articulation levels have various examples in different sorts of thyroid sease.STAT3 articulation is limited to epithelial cells in tissue tests of patients with Hashimoto's sickness [31].Bosom disease cells have higher STAT3 articulation that prompts cancer development by restraining apoptosis-related qualities like C-Myc,BCL-2, and CCND1 [32].Various inter leukins can adjust STAT3 articulation. For model, IL-35 inhibits ordinary White blood cells that initiate STAT3,what's more; STAT1and IL-8 advance bosom disease movement by initiating STAT3. In contrast, IL-17 diminishes STAT3 articulation [33-35]. Initiation of STAT3 by phosphorylation at Tyr 705 site causes human tumors with epithelial beginning like Head and Neck Squamous Cell Carcinoma (HNSCC) with an unfortunate visualization and metastasis [36,37].
Concentrates on in ovarian malignant growth cell lines have shown that STAT3 is phosphorylated and initiated, prompting a less fortunate forecast of sickness with metastasis [38,39].Ovarian malignant growth protection from paclitaxel can be ascribed to STAT3 over action, which can be decreased by restraining the obstruction of this disease to treatment [40].
The clonal cancer of hematopoietic cells known as leukaemia is brought on by alterations in stem cells. Increased cell proliferation and altered or prevented differentiation are two of these alterations. Other symptoms like infection and repeated bleeding result from changes in the amount of blood cells. Leukemia is treated with chemotherapy, although this method is quite cytotoxic. After the treatment sessions, there is a substantial likelihood of recurrence [41].
Leukemia has such a high mortality rate that 26,000 new cases are found each year in the United States. Finding the best course of treatment is therefore not only challenging but also quite effective [42].Leukemia may result from excessive growth factor and cytokine-induced STAT3 pathway autocrine and paracrine activity. Chemotherapy can be replaced with treatments that are more successful since we can block this route with antibodies and other substances. Research on mice has revealed that STAT3 inhibition is connected to reduced toxicity. [22].
On samples from ALL and AML patients, the first investigations to identify STAT3 hyperactivity in leukaemia were carried out. In these research, electrophoretic mobility shift tests were used to determine the status of phosphorylation. As a result, STAT1, 3, and 5 activities were seen in patients with AML, while STAT1 and 5 activities were seen in individuals with ALL [43]. Inhibiting the STAT3 pathway increases cancer cell death while not being as harmful to the remaining healthy cells as chemotherapy. It does not elicit resistance and is entirely particular.
Tyrosine kinase receptors (TKR) including EGFR, PDGFR, fibroblast growth factor (FGFR), and insulin-like growth factor receptor (IGFR), receptor linked kinases like JAK, and non-receptor kinases like src and abl phosphorylate STAT3 at Tyr705 and Ser727 [2].In this manner, STAT3 activation can result in the formation of a dimer and gene expression. Genes like c-Myc, Bcl-xL, and MCL-1 that are involved in proliferation and survival are controlled by STAT3 [45]. After being exposed to a cytokine for 15 to 60 minutes, STAT3 phosphorylation reaches its maximum. After that, a negative control is carried out in two ways using its dephosphorylation: via Suppressor of Cytokine Signaling (SOCS), which transcriptionally regulates STAT3, and without it.
Important biological processes carried out by STAT3 can become hampered by deletion or overactivation. Although it was formerly believed that the protein could only be activated by the IL-6 signal, it has since been discovered that STAT3 may also be triggered by a variety of other cytokines and growth factors [46]. Studies have revealed that whereas healthy cells can survive at very low levels of STAT3 and 5 signalling and can grow through alternative growth mechanisms, cancer cells are more dependent on the activity of STAT than healthy cells. As a result, the inhibition of STAT3 and 5 leads to higher apoptosis in these cells. This protein and its components have so recently attracted a lot of interest for the treatment of numerous ailments [6].
Peptide hormones are frequently the first step in the signalling pathway, which connects to three different receptor types, including kinase receptors and protein G receptors. STAT3 must first be phosphorylated, which results in protein-protein interactions, in order to transmit the message from the membrane to the nucleus. Tyr705 phosphorylation of STAT3 aids in the formation of monomers or hetero-dimers that can attach to the tail of the SH2 domain [47].
STAT3 pathway inhibitors are designed to research synthetic compounds that can specifically target the STAT3 molecule or various functional protein regions like the DNA-binding SH2 domain. Certain of these compounds can stop STAT3 from becoming a dimer. Some of them have an impact on the downstream pathways and genes, while others block the passage of messages from the membrane to the nucleus. The ideal molecules are those that no longer interact with STAT molecules and whose upstream pathways directly influence the STAT molecule [48].
As was already discussed, STAT3 needs to be phosphorylated in order to form homodimers or heterodimers and transmit signals from the plasma membrane to the nucleus. By binding to and deforming the SH2 region, peptides can specifically target the STAT3 signalling pathway. It stops a dimer from forming It prevents the monomer from becoming a dimer. Synthesized peptides have a phosphorylated PY sequence that allows them to attach to the SH2 area and stop dimmers from forming [10]. The first study to use pro-pTyr-Leu-Lys-Thr-Lys-derived phosphopeptides to block this pathway was conducted by Turkson et al. [6].
Theoretically, this strategy could be successful, however since SH2 domains are shared by a variety of signalling molecules, targeting STAT3 directly is not a smart idea.By attaching its SH2 region to the remaining phosphotyrosines of specific proteins, such as gp130, Lysosomal Inhibitor Factor Receptor (LIFR), epidermal growth factor receptor, IL-10R, and G-CSF receptor, STAT3 can stay in the signalling pathway. Ren et al. [49] created peptidomimetics from peptides, which are molecules with improved properties to create a scaffolding with XpYL as the main structure [10], in order to inhibit this part of the STAT3 signalling pathway due to its cell permeability as well as low metabolic and pharmacokinetic properties. Molecules produced from STAT3 Tyr705 called phosphopeptides have the ability to bind to and inhibit phosphotyrosine ligands [11]. Another inhibitor is PDP, a phosphor-do-decapeptide that inhibits STAT3's DNA binding site by interacting to nonphosphorylated STAT3 and has Y1068 in its EGFR sequence [50].
Due to pharmacokinetic restrictions, the body's inability to metabolise peptides, and their limited membrane permeability, a group of novel compounds known as small molecules were created in peptidomics to block this process. These compounds are highly permeable and belong to the largest class of inhibitors.
Small molecules are particularly interesting to investigate because they are found inside the cell [3,51].Similar to peptides, these small compounds inhibit STAT and stop the formation of STAT3-STAT3 dimers by targeting the pTyr-SH2 region [52]. Small molecules like the STA-21 can be created naturally.The examination and growth of a species of Streptomyces rimosus bacterium revealed this substance to be an antibiotic.At varying concentrations, the tetrangomycin analogue STA-21 can structurally block STAT3; at a dose of 20 M, it can inhibit the DNA binding area, and at a dose of 20 M - 30 M, it expresses STAT3-related genes and prevents cell proliferation [51,53].
One of the most crucial channels for delivering extracellular signals to cell nuclei is the STAT signalling system, which, when hyperactive, can lead to a number of malignancies. For this pathway, several inhibitors have been developed, and STAT3 and STAT5 pathway inhibitors are currently the subject of more research in order to prepare for clinical trials. Additionally, the STAT3 pathway has less adverse effects and might have a promising therapeutic future because it is blocked in mature cells.
1. Buettner R, Mora LB, Jove R. Activated STAT signaling in human tumors provides novel molecular targets for therapeutic intervention. Clin Cancer Res. 2002;8(4):945- 54.
2. Chai EZ, Shanmugam MK, Arfuso F, Dharmarajan A, Wang C, Kumar AP, et al. Targeting transcription factor STAT3 for cancer prevention and therapy. Pharmacol Ther. 2016;162:86-97.
3. Ward AC. STAT Inhibitors in Cancer: Springer; 2016.
4. Siveen KS, Sikka S, Surana R, Dai X, Zhang J, Kumar AP, et al. Targeting the STAT3 signaling pathway in cancer: role of synthetic and natural inhibitors. Biochim Biophys Acta. 2014;1845(2):136-54.
5. Sgrignani J, Garofalo M, Matkovic M, Merulla J, Catapano CV, Cavalli A. Structural Biology of STAT3 and Its Implications for Anticancer Therapies Development. Int J Mol Sci. 2018;19(6):1591.
6. Furqan M, Akinleye A, Mukhi N, Mittal V, Chen Y, Liu D. STAT inhibitors for cancer therapy. J Hematol Oncol. 2013;6:90.
7. Shi Y, Zhang Z, Qu X, Zhu X, Zhao L, Wei R, et al. Roles of STAT3 in leukemia. Int J Oncol 2018;53(1):7-20.
8. Hu T, Yeh JE, Pinello L, Jacob J, Chakravarthy S, Yuan GC, et al. Impact of the N-terminal domain of STAT3 in STAT3-dependent transcriptional activity. Mol Cell Biol. 2015;35(19):3284-300.
9. Pellegrini S, Dusanter‐Fourt I. The structure, regulation and function of the Janus kinases (JAKs) and the signal transducers and activators of transcription (STATs). Eur J biochem. 1997;248(3):615-33.
10. Johnston PA, Grandis JR. STAT3 signaling: anticancer strategies and challenges. Mol Interv. 2011;11(1):18-26.
11. Jing N, Tweardy DJ. Targeting Stat3 in cancer therapy. Anticancer drugs 2005;16(6):601-7.
12. Schust J, Sperl B, Hollis A, Mayer TU, Berg T. Stattic: a small-molecule inhibitor of STAT3 activation and dimerization. Chem Biol. 2006;13(11):1235-42.
13. Wang Y, Qu A, Wang H. Signal transducer and activator of transcription 4 in liver diseases. Int J Biol Sci 2015;11(4):448-55.
14. Wurster AL, Tanaka T, Grusby MJ. The biology of Stat4 and Stat6. Oncogene. 2000;19(21):2577-84.
15. Schindler C, Plumlee C. Inteferons pen the JAK-STAT pathway. Semin Cell Dev Biol. 2008;19(4):311-8.
16. Kosan C, Ginter T, Heinzel T, Krämer OH. STAT5 acetylation: Mechanisms and consequences for immunological control and leukemogenesis. JAKSTAT. 2013;2(4):e26102.
17. Walford HH, Doherty TA. STAT6 and lung inflammation. JAKSTAT. 2013;2(4):e25301. 18. Levy DE, Lee CK. What does Stat3 do? J Clin Invest. 2002;109(9):1143-8.
18. Levy DE, Lee CK. What does Stat3 do? J Clin Invest. 2002;109(9):1143-8.
19. Real PJ, Sierra A, de Juan A, Segovia JC, Lopez-Vega JM, Fernandez-Luna JL. Resistance to chemotherapy via Stat3-dependent overexpression of Bcl-2 in metastatic breast cancer cells. Oncogene 2002;21(50):7611-8
20. Glienke W, Maute L, Wicht J, Bergmann L. Curcumin inhibits constitutive STAT3 phosphorylation in human pancreatic cancer cell lines and downregulation of survivin/BIRC5 gene expression. Cancer Invest. 2010;28(2):166-71.
21. Darnell JE, Kerr IM, Stark GR. Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science. 1994;264(5164):1415-21.
22. Bromberg JF, Wrzeszczynska MH, Devgan G, Zhao Y, Pestell RG, Albanese C, et al. Stat3 as an oncogene. Cell. 1999;98(3):295-303.
23. Niu G, Heller R, Catlett-Falcone R, Coppola D, Jaroszeski M, Dalton W, et al. Gene therapy with dominant-negative Stat3 suppresses growth of the murine melanoma B16 tumor in vivo. Cancer Res. 1999;59(20):5059-63.
24. Groner B, Lucks P, Borghouts C. The function of Stat3 in tumor cells and their microenvironment. Semin Cell Dev Biol. 2008;19(4):341-50.
25. Chen Z, Han ZC. STAT3: a critical transcription activator in angiogenesis. Med Res Rev. 2008;28(2):185-200.
26. Plate KH, Breier G, Weich HA, Risau W. Vascular endothelial growth factor is a potential tumour angiogenesis factor in human gliomas in vivo. Nature. 1992;359(6398):845-8.
27. Grunstein J, Roberts WG, Mathieu-Costello O, Hanahan D, Johnson RS. Tumorderived expression of vascular endothelial growth factor is a critical factor in tumor expansion and vascular function. Cancer Res. 1999;59(7):1592-8.
28. Kamran MZ, Patil P, Gude RP. Role of STAT3 in cancer metastasis and translational advances. Biomed Res Int. 2013;2013:421821.
29. Couto JP, Daly L, Almeida A, Knauf JA, Fagin JA, Sobrinho-Simões M, et al. STAT3 negatively regulates thyroid tumorigenesis. Proc Natl Acad Sci. 2012;109(35):E2361-E70.
30. Sosonkina N, Starenki D, Park JI. The role of STAT3 in thyroid cancer. Cancers. 2014;6(1):526-44.
31. Staab J, Barth PJ, Meyer T. Cell-type-specific expression of STAT transcription factors in tissue samples from patients with lymphocytic thyroiditis. Endocr Pathol. 2012;23(3):141-50.
32. Ma JH, Qin L, Li X. Role of STAT3 signaling pathway in breast cancer. Cell Commun Signal. 2020;18(1):1-13.
33. Ma M, Huang W, Kong D. IL-17 inhibits the accumulation of myeloid-derived suppressor cells in breast cancer via activating STAT3. Int Immunopharmacol. 2018;59:148-56.
34. Valeta-Magara A, Gadi A, Volta V, Walters B, Arju R, Giashuddin S, et al. Inflammatory Breast Cancer Promotes Development of M2 Tumor-Associated Macrophages and Cancer Mesenchymal Cells through a Complex Chemokine Network. Cancer Res. 2019;79(13):3360-71.
35. Tong ZT, Cai MY, Wang XG, Kong LL, Mai SJ, Liu YH, et al. EZH2 supports nasopharyngeal carcinoma cell aggressiveness by forming a co-repressor complex with HDAC1/HDAC2 and Snail to inhibit E-cadherin. Oncogene. 2012;31(5):583-94.
36. Wang Y, Wang S, Wu Y, Ren Y, Li Z, Yao X, et al. Suppression of the growth and invasion of human head and neck squamous cell carcinomas via regulating STAT3 signaling and the miR-21/β-catenin axis with HJC0152. Mol Cancer Ther. 2017;16(4):578-90.
37. Colomiere M, Findlay J, Ackland L, Ahmed N. Epidermal growth factor-induced ovarian carcinoma cell migration is associated with JAK2/STAT3 signals and changes in the abundance and localization of alpha6beta1 integrin. Int J Biochem Cell Biol. 2009;41(5):1034-45.
38. Huang M, Page C, Reynolds RK, Lin J. Constitutive activation of STAT3 oncogene product in human ovarian carcinoma cells. Gynecol Oncol. 2000;79(1):67-73.
39. Duan Z, Foster R, Bell DA, Mahoney J, Wolak K, Vaidya A, et al. Signal transducers and activators of transcription 3 pathway activation in drug-resistant ovarian cancer. Clin Cancer Res. 2006;12(17):5055-63.
40. Kanna R, Choudhary G, Ramachandra N, Steidl U, Verma A, Shastri A. STAT3 inhibition as a therapeutic strategy for leukemia. Leuk Lymphoma 2018;59(9):2068- 74.
41. Lin TS, Mahajan S, Frank DA. STAT signaling in the pathogenesis and treatment of leukemias. Oncogene. 2000;19(21):2496-504.
42. Frank DA. STAT signaling in the pathogenesis and treatment of cancer. Mol Med. 1999;5(7):432-56.
43. Fagard R, Metelev V, Souissi I, Baran-Marszak F. STAT3 inhibitors for cancer therapy: Have all roads been explored? JAKSTAT. 2013;2(1):e22882.
44. Gharibi T, Babaloo Z, Hosseini A, Abdollahpour-Alitappeh M, Hashemi V, Marofi F, et al. Targeting STAT3 in cancer and autoimmune diseases. Eur J Pharmacol. 2020;878:173107.
45. Cimica V, Chen H-C, Iyer JK, Reich NC. Dynamics of the STAT3 transcription factor: nuclear import dependent on Ran and importin-β1. PloS One. 2011;6(5):e20188.
46. Shao H, Xu X, Mastrangelo MAA, Jing N, Cook RG, Legge GB, et al. Structural requirements for signal transducer and activator of transcription 3 binding to phosphotyrosine ligands containing the YXXQ motif. J Biol Chem. 2004;279(18):18967-73.
47. Deng J, Grande F, Neamati N. Small molecule inhibitors of Stat3 signaling pathway. Curr Cancer Drug Targets. 2007;7(1):91-107.
48. Auzenne EJ, Klostergaard J, Mandal PK, Liao WS, Lu Z, Gao F, et al. A phosphopeptide mimetic prodrug targeting the SH2 domain of Stat3 inhibits tumor growth and angiogenesis. J Exp Ther Oncol. 2012;10(2):155-62.
49. Ren Z, Cabell LA, Schaefer TS, McMurray JS. Identification of a high-affinity phosphopeptide inhibitor of Stat3. Bioorg Med Chem Lett. 2003;13(4):633-6.
50. Yue P, Turkson J. Targeting STAT3 in cancer: how successful are we? Expert Opin Investig Drugs. 2009;18(1):45-56.
51. Zhao M, Jiang B, Gao FH. Small molecule inhibitors of STAT3 for cancer therapy. Curr Med Chem. 2011;18(26):4012-8.
52. Debnath B, Xu S, Neamati N. Small molecule inhibitors of signal transducer and activator of transcription 3 (Stat3) protein. J Med Chem. 2012;55(15):6645-68.
53. Kiessling A, Sperl B, Hollis A, Eick D, Berg T. Selective inhibition of c-Myc/Max dimerization and DNA binding by small molecules. Chem Biol. 2006;13(7):745-51.
54. Goel A, Kunnumakkara AB, Aggarwal BB. Curcumin as “Curecumin”: from kitchen to clinic. Biochem Pharmacol. 2008;75(4):787-809.
55. Shen L, Ji HF. Theoretical study on physicochemical properties of curcumin. Spectrochim Acta A Mol Biomol Spectrosc. 2007;67(3-4):619-23.
56. Alexandrow MG, Song LJ, Altiok S, Gray J, Haura EB, Kumar NB. Curcumin: a novel STAT3 pathway inhibitor for chemoprevention of lung cancer. Eur J Cancer Pre. 2012;21(5):407-12.
57. Blasius R, Reuter S, Henry E, Dicato M, Diederich M. Curcumin regulates signal transducer and activator of transcription (STAT) expression in K562 cells. Biochem Pharmacol. 2006;72(11):1547-54.
58. Morishita R, Tomita N, Kaneda Y, Ogihara T. Molecular therapy to inhibit NFκB activation by transcription factor decoy oligonucleotides. Curr Opin Pharmacol. 2004;4(2):139-46.
59. Gu J, Li G, Sun T, Su Y, Zhang X, Shen J, et al. Blockage of the STAT3 signaling pathway with a decoy oligonucleotide suppresses growth of human malignant glioma cells. J Neurooncol. 2008;89(1):9.
60. Sen M, Tosca PJ, Zwayer C, Ryan MJ, Johnson JD, Knostman KA, et al. Lack of toxicity of a STAT3 decoy oligonucleotide. Cancer Chemother Pharmacol. 2009;63(6):983-95.
61. Bielinska A, Shivdasani RA, Zhang L, Nabel GJ. Regulation of gene expression with doubl
Zohre Yaaghoubi . Inhibitors of STATs in Cancer Therapy Methods. World Journal Of Hematology And Oncology 2022.