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Molecule Details

General Information of the Molecule
Name
STAT factor 3 (STAT3)
Synonyms
Signal transducer and activator of transcription 3; Acute-phase response factor; APRF
Gene Name
STAT3
Gene ID
6774
Sequence
MAQWNQLQQLDTRYLEQLHQLYSDSFPMELRQFLAPWIESQDWAYAASKESHATLVFHNL
LGEIDQQYSRFLQESNVLYQHNLRRIKQFLQSRYLEKPMEIARIVARCLWEESRLLQTAA
TAAQQGGQANHPTAAVVTEKQQMLEQHLQDVRKRVQDLEQKMKVVENLQDDFDFNYKTLK
SQGDMQDLNGNNQSVTRQKMQQLEQMLTALDQMRRSIVSELAGLLSAMEYVQKTLTDEEL
ADWKRRQQIACIGGPPNICLDRLENWITSLAESQLQTRQQIKKLEELQQKVSYKGDPIVQ
HRPMLEERIVELFRNLMKSAFVVERQPCMPMHPDRPLVIKTGVQFTTKVRLLVKFPELNY
QLKIKVCIDKDSGDVAALRGSRKFNILGTNTKVMNMEESNNGSLSAEFKHLTLREQRCGN
GGRANCDASLIVTEELHLITFETEVYHQGLKIDLETHSLPVVVISNICQMPNAWASILWY
NMLTNNPKNVNFFTKPPIGTWDQVAEVLSWQFSSTTKRGLSIEQLTTLAEKLLGPGVNYS
GCQITWAKFCKENMAGKGFSFWVWLDNIIDLVKKYILALWNEGYIMGFISKERERAILST
KPPGTFLLRFSESSKEGGVTFTWVEKDISGKTQIQSVEPYTKQQLNNMSFAEIIMGYKIM
DATNILVSPLVYLYPDIPKEEAFGKYCRPESQEHPEADPGSAAPYLKTKFICVTPTTCSN
TIDLPMSPRTLDSLMQFGNNGEGAEPSAGGQFESLTFDMELTSECATSPM
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Function
Signal transducer and transcription activator that mediates cellular responses to interleukins, KITLG/SCF, LEP and other growth factors. Once activated, recruits coactivators, such as NCOA1 or MED1, to the promoter region of the target gene. May mediate cellular responses to activated FGFR1, FGFR2, FGFR3 and FGFR4. Upon activation of IL6ST/gp130 signaling by interleukin-6 (IL6), binds to the IL6-responsive elements identified in the promoters of various acute-phase protein genes. Activated by IL31 through IL31RA. Acts as a regulator of inflammatory response by regulating differentiation of naive CD4(+) T-cells into T-helper Th17 or regulatory T-cells (Treg): deacetylation and oxidation of lysine residues by LOXL3, leads to disrupt STAT3 dimerization and inhibit its transcription activity. Involved in cell cycle regulation by inducing the expression of key genes for the progression from G1 to S phase, such as CCND1. Mediates the effects of LEP on melanocortin production, body energy homeostasis and lactation (By similarity). May play an apoptotic role by transctivating BIRC5 expression under LEP activation. Cytoplasmic STAT3 represses macroautophagy by inhibiting EIF2AK2/PKR activity. Plays a crucial role in basal beta cell functions, such as regulation of insulin secretion (By similarity).
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Uniprot ID
STAT3_HUMAN
Pfam
PF00017 ; PF01017 ; PF02864 ; PF02865
KEGG ID
hsa6774
TTD ID
T29130
A List of Drug Combination(s) Able to Regulate This Molecule
          Expression Regulation     Click to Show/Hide the Drug Combination Regulating This Molecule
                 Down-regulation     Click to Show/Hide
                    Drug Combination 1 Down-regulating the Expression of This Molecule [1]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Name Plumbagin   NP Info  + Celecoxib   Drug Info 
                    Structure +
                    Drug Combination 2 Down-regulating the Expression of This Molecule [2]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Name Triptolide   NP Info  + AMD3100   Drug Info 
                    Structure +
                    Drug Combination 3 Down-regulating the Expression of This Molecule [3]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Name Shikonin   NP Info  + Gefitinib   Drug Info 
                    Structure +
                    Drug Combination 4 Down-regulating the Expression of This Molecule [4]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Name Ursolic acid   NP Info  + Gemcitabine   Drug Info 
                    Structure +
                    Drug Combination 5 Down-regulating the Expression of This Molecule [5]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Name Cardamonin   NP Info  + Doxorubicin   Drug Info 
                    Structure +
                    Drug Combination 6 Down-regulating the Expression of This Molecule [6]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Name Curcumin   NP Info  + Thalidomide   Drug Info 
                    Structure +
                    Drug Combination 7 Down-regulating the Expression of This Molecule [7]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Name Cardamonin   NP Info  + 5-fluorouracil   Drug Info 
                    Structure +
                 Up-regulation     Click to Show/Hide
                    Drug Combination 1 Up-regulating the Expression of This Molecule [32]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Name Arctigenin   NP Info  + Cisplatin   Drug Info 
                    Structure +
                    Drug Combination 2 Up-regulating the Expression of This Molecule [33]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Name Anisodamine   NP Info  + Neostigmine   Drug Info 
                    Structure +
                    Drug Combination 3 Up-regulating the Expression of This Molecule [34]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Name Arctigenin   NP Info  + Doxorubicin   Drug Info 
                    Structure +
          Phosphorylation Regulation     Click to Show/Hide the Drug Combination Regulating This Molecule
                 Down-regulation     Click to Show/Hide
                    Drug Combination 1 Down-regulating the Phosphorylation of This Molecule [8]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Name Silibinin   NP Info  + Indole-3-carbinol   Drug Info 
                    Structure +
                    Drug Combination 2 Down-regulating the Phosphorylation of This Molecule [9]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Name Resveratrol   NP Info  + 5-fluorouracil   Drug Info 
                    Structure +
                    Drug Combination 3 Down-regulating the Phosphorylation of This Molecule [10]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Name Curcumin   NP Info  + Bortezomib   Drug Info 
                    Structure +
                    Drug Combination 4 Down-regulating the Phosphorylation of This Molecule [11]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Name Shikonin   NP Info  + TNF-related apoptosis inducing ligand    Drug Info 
                    Structure +
                    Drug Combination 5 Down-regulating the Phosphorylation of This Molecule [12]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Name Ursodeoxycholic acid   NP Info  + Sorafenib   Drug Info 
                    Structure +
                    Drug Combination 6 Down-regulating the Phosphorylation of This Molecule [13]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Name Schisandrin A   NP Info  + Doxorubicin   Drug Info 
                    Structure +
                    Drug Combination 7 Down-regulating the Phosphorylation of This Molecule [14]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Name Morin   NP Info  + MST312   Drug Info 
                    Structure +
                    Drug Combination 8 Down-regulating the Phosphorylation of This Molecule [15]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Name Celastrol   NP Info  + Erlotinib   Drug Info 
                    Structure +
                    Drug Combination 9 Down-regulating the Phosphorylation of This Molecule [16]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Name Tanshinone IIA   NP Info  + Sorafenib   Drug Info 
                    Structure +
                    Drug Combination 10 Down-regulating the Phosphorylation of This Molecule [17]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Name Curcumin   NP Info  + Sorafenib   Drug Info 
                    Structure +
                    Drug Combination 11 Down-regulating the Phosphorylation of This Molecule [15]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Name Celastrol   NP Info  + Gefitinib   Drug Info 
                    Structure +
                    Drug Combination 12 Down-regulating the Phosphorylation of This Molecule [18]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Name Gallic acid   NP Info  + Cisplatin   Drug Info 
                    Structure +
                    Drug Combination 13 Down-regulating the Phosphorylation of This Molecule [19]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Name Piperine   NP Info  + Mitomycin C   Drug Info 
                    Structure +
                    Drug Combination 14 Down-regulating the Phosphorylation of This Molecule [20]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Name Toosendanin   NP Info  + Regorafenib   Drug Info 
                    Structure +
                    Drug Combination 15 Down-regulating the Phosphorylation of This Molecule [21]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Name Elemene   NP Info  + Cisplatin   Drug Info 
                    Structure +
                    Drug Combination 16 Down-regulating the Phosphorylation of This Molecule [22]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Name Paclitaxel   NP Info  + Napabucasin   Drug Info 
                    Structure +
                    Drug Combination 17 Down-regulating the Phosphorylation of This Molecule [23]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Name Apigenin   NP Info  + Cetuximab   Drug Info 
                    Structure +
                    Drug Combination 18 Down-regulating the Phosphorylation of This Molecule [24]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Name Arsenic trioxide   NP Info  + Cisplatin   Drug Info 
                    Structure +
                    Drug Combination 19 Down-regulating the Phosphorylation of This Molecule [25]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Name Flavopiridol   NP Info  + Bortezomib   Drug Info 
                    Structure +
                    Drug Combination 20 Down-regulating the Phosphorylation of This Molecule [26]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Name Ursolic acid   NP Info  + Capecitabine   Drug Info 
                    Structure +
                    Drug Combination 21 Down-regulating the Phosphorylation of This Molecule [27]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Name Silibinin   NP Info  + Sorafenib   Drug Info 
                    Structure +
                    Drug Combination 22 Down-regulating the Phosphorylation of This Molecule [28]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Name Galangin   NP Info  + Cisplatin   Drug Info 
                    Structure +
                    Drug Combination 23 Down-regulating the Phosphorylation of This Molecule [29]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Name Resveratrol   NP Info  + Temozolomide   Drug Info 
                    Structure +
                    Drug Combination 24 Down-regulating the Phosphorylation of This Molecule [30]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Name Pterostilbene   NP Info  + Osimertinib   Drug Info 
                    Structure +
                    Drug Combination 25 Down-regulating the Phosphorylation of This Molecule [31]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Name Capsaicin   NP Info  + Sorafenib   Drug Info 
                    Structure +
                 Up-regulation     Click to Show/Hide
                    Drug Combination 1 Up-regulating the Phosphorylation of This Molecule [35]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Name Lycopene   NP Info  + Anti-PD-1 antibody   Drug Info 
                    Structure +
Natural Product(s) of This Target
1 Acitretin  NP Info  Approved Homo sapiens
2 Cryptotanshinone  NP Info  Investigative Salvia miltiorrhiza
3 Cucurbitacin I  NP Info  Investigative Citrullus lanatus
4 Osthole  NP Info  Investigative Angelica pubescens
5 Toosendanin  NP Info  Investigative Melia azedarach
Drug(s) of This Target
1 Dicyclohexylcarbodiimide  Drug Info  Investigative Prostate cancer
2 Napabucasin  Drug Info  Phase 3 Pancreatic cancer
3 S3I-201  Drug Info  Investigative Lupus nephritis
References
Reference 1 Synergistic inhibitory effects of Celecoxib and Plumbagin on melanoma tumor growth. Cancer Lett. 2017 Jan 28;385:243-250.
Reference 2 AMD3100 combined with triptolide inhibit proliferation, invasion and metastasis and induce apoptosis of human U2OS osteosarcoma cells. Biomed Pharmacother. 2017 Feb;86:677-685.
Reference 3 Shikonin enhances sensitization of gefitinib against wild-type EGFR non-small cell lung cancer via inhibition PKM2/stat3/cyclinD1 signal pathway. Life Sci. 2018 Jul 1;204:71-77.
Reference 4 Ursolic acid inhibits the growth of human pancreatic cancer and enhances the antitumor potential of gemcitabine in an orthotopic mouse model through suppression of the inflammatory microenvironment. Oncotarget. 2016 Mar 15;7(11):13182-96.
Reference 5 Cardamonin reduces chemotherapy-enriched breast cancer stem-like cells in vitro and in vivo. Oncotarget. 2016 Jan 5;7(1):771-85.
Reference 6 Curcumin Combined with Thalidomide Reduces Expression of STAT3 and Bcl-xL, Leading to Apoptosis in Acute Myeloid Leukemia Cell Lines. Drug Des Devel Ther. 2020 Jan 15;14:185-194.
Reference 7 Cardamonin, a natural chalcone, reduces 5-fluorouracil resistance of gastric cancer cells through targeting Wnt/beta-catenin signal pathway. Invest New Drugs. 2020 Apr;38(2):329-339.
Reference 8 Enhanced inhibition of lung adenocarcinoma by combinatorial treatment with indole-3-carbinol and silibinin in A/J mice. Carcinogenesis. 2011 Apr;32(4):561-7.
Reference 9 Effect of resveratrol and in combination with 5-FU on murine liver cancer. World J Gastroenterol. 2004 Oct 15;10(20):3048-52.
Reference 10 Curcumin in combination with bortezomib synergistically induced apoptosis in human multiple myeloma U266 cells. Mol Oncol. 2008 Dec;2(4):317-26.
Reference 11 Shikonin sensitizes A549 cells to TRAIL-induced apoptosis through the JNK, STAT3 and AKT pathways. BMC Cell Biol. 2018 Dec 29;19(1):29.
Reference 12 Synergistic effect of ursodeoxycholic acid on the antitumor activity of sorafenib in hepatocellular carcinoma cells via modulation of STAT3 and ERK. Int J Mol Med. 2018 Nov;42(5):2551-2559.
Reference 13 Schisandrin A reverses doxorubicin-resistant human breast cancer cell line by the inhibition of P65 and Stat3 phosphorylation. Breast Cancer. 2018 Mar;25(2):233-242.
Reference 14 Combination treatment with flavonoid morin and telomerase inhibitor MST?312 reduces cancer stem cell traits by targeting STAT3 and telomerase. Int J Oncol. 2016 Aug;49(2):487-98.
Reference 15 Celastrol improves the therapeutic efficacy of EGFR-TKIs for non-small-cell lung cancer by overcoming EGFR T790M drug resistance. Anticancer Drugs. 2018 Sep;29(8):748-755.
Reference 16 Synergistic antitumor effects of tanshinone IIA and sorafenib or its derivative SC-1 in hepatocellular carcinoma cells. Onco Targets Ther. 2018 Mar 29;11:1777-1785.
Reference 17 Combinatorial anticancer effects of curcumin and sorafenib towards thyroid cancer cells via PI3K/Akt and ERK pathways. Nat Prod Res. 2016 Aug;30(16):1858-61.
Reference 18 Gallic acid has anticancer activity and enhances the anticancer effects of cisplatin in non?small cell lung cancer A549 cells via the JAK/STAT3 signaling pathway. Oncol Rep. 2019 Mar;41(3):1779-1788.
Reference 19 Piperine (PP) enhanced mitomycin-C (MMC) therapy of human cervical cancer through suppressing Bcl-2 signaling pathway via inactivating STAT3/NF-KappaB. Biomed Pharmacother. 2017 Dec;96:1403-1410.
Reference 20 Synergistic effect of toosendanin and regorafenib against cell proliferation and migration by regulating WWOX signaling pathway in hepatocellular carcinoma. Phytother Res. 2021 May 31.
Reference 21 beta-Elemene, a novel plant-derived antineoplastic agent, increases cisplatin chemosensitivity of lung tumor cells by triggering apoptosis. Oncol Rep. 2009 Jul;22(1):161-70.
Reference 22 Targeted activation of Stat3 in combination with paclitaxel results in increased apoptosis in epithelial ovarian cancer cells and a reduced tumour burden. Cell Prolif. 2020 Jan;53(1):e12719.
Reference 23 Apigenin enhances the antitumor effects of cetuximab in nasopharyngeal carcinoma by inhibiting EGFR signaling. Biomed Pharmacother. 2018 Jun;102:681-688.
Reference 24 Co-application of arsenic trioxide (As2O3) and cisplatin (CDDP) on human SY-5Y neuroblastoma cells has differential effects on the intracellular calcium concentration ([Ca2+]i) and cytotoxicity. Neurotoxicology. 2009 Mar;30(2):194-202.
Reference 25 Bortezomib and flavopiridol interact synergistically to induce apoptosis in chronic myeloid leukemia cells resistant to imatinib mesylate through both Bcr/Abl-dependent and -independent mechanisms. Blood. 2004 Jul 15;104(2):509-18.
Reference 26 Ursolic acid inhibits growth and metastasis of human colorectal cancer in an orthotopic nude mouse model by targeting multiple cell signaling pathways: chemosensitization with capecitabine. Clin Cancer Res. 2012 Sep 15;18(18):4942-53.
Reference 27 Combined treatment with sorafenib and silibinin synergistically targets both HCC cells and cancer stem cells by enhanced inhibition of the phosphorylation of STAT3/ERK/AKT. Eur J Pharmacol. 2018 Aug 5;832:39-49.
Reference 28 Effects of flavonoids on cisplatin-induced apoptosis of HL-60 and L1210 leukemia cells. Leuk Res. 2003 Jan;27(1):65-72.
Reference 29 Resveratrol enhances the antitumor effects of temozolomide in glioblastoma via ROS-dependent AMPK-TSC-mTOR signaling pathway. CNS Neurosci Ther. 2012 Jul;18(7):536-46.
Reference 30 Osimertinib and pterostilbene in EGFR-mutation-positive non-small cell lung cancer (NSCLC). Int J Biol Sci. 2019 Sep 7;15(12):2607-2614.
Reference 31 Capsaicin enhances the antitumor activity of sorafenib in hepatocellular carcinoma cells and mouse xenograft tumors through increased ERK signaling. Acta Pharmacol Sin. 2018 Mar;39(3):438-448.
Reference 32 Arctigenin enhances chemosensitivity to cisplatin in human nonsmall lung cancer H460 cells through downregulation of survivin expression. J Biochem Mol Toxicol. 2014 Jan;28(1):39-45.
Reference 33 Combined administration of anisodamine and neostigmine rescued acute lethal crush syndrome through Alpha7nAChR-dependent JAK2-STAT3 signaling. Sci Rep. 2016 Nov 22;6:37709.
Reference 34 Arctigenin Enhances the Cytotoxic Effect of Doxorubicin in MDA-MB-231 Breast Cancer Cells. Int J Mol Sci. 2020 Apr 23;21(8):2997.
Reference 35 Lycopene improves the efficiency of anti-PD-1 therapy via activating IFN signaling of lung cancer cells. Cancer Cell Int. 2019 Mar 21;19:68.
Reference 36 Effects of acitretin on the expression of signaling pathway-related genes in epidermal squamous-cell carcinoma cells. Zhonghua Zhong Liu Za Zhi. 2006 Jan;28(1):21-4.
Reference 37 Cryptotanshinone protects against pulmonary fibrosis through inhibiting Smad and STAT3 signaling pathways. Pharmacol Res. 2019 Sep;147:104307.
Reference 38 Cucurbitacin I inhibits tumorigenic ability and enhances radiochemosensitivity in nonsmall cell lung cancer-derived CD133-positive cells. Cancer. 2011 Jul 1;117(13):2970-85.
Reference 39 Osthole inhibits triple negative breast cancer cells by suppressing STAT3. J Exp Clin Cancer Res. 2018 Dec 22;37(1):322.
Reference 40 Toosendanin demonstrates promising antitumor efficacy in osteosarcoma by targeting STAT3. Oncogene. 2017 Nov 23;36(47):6627-6639.
Reference 41 STAT3 mediates C6-ceramide-induced cell death in chronic lymphocytic leukemia. Signal Transduct Target Ther. 2017 Oct 27;2:17051.
Reference 42 Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
Reference 43 A STAT inhibitor patent review: progress since 2011.Expert Opin Ther Pat. 2015;25(12):1397-421.
Cite NPCDR
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Correspondence

X. N. Sun, Y. T. Zhang, Y. Zhou, X. C. Lian, L. L. Yan, T. Pan, T. Jin, H. Xie, Z. M. Liang, W. Q. Qiu, J. X. Wang, Z. R. Li, F. Zhu*, X. B. Sui*. NPCDR: natural product-based drug combination and its disease-specific molecular regulation. Nucleic Acids Research. 50(D1): 1324-1333 (2020). PMID: 34664659

Prof. Feng ZHU  (zhufeng@zju.edu.cn)

College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China


Prof. Xinbing SUI  (hzzju@hznu.edu.cn)

School of Pharmacy and Department of Medical Oncology, the Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, China