1521-0081/72/2/486–526$35.00 https://doi.org/10.1124/pr.119.018440 PHARMACOLOGICAL REVIEWS Pharmacol Rev 72:486–526, April 2020 Copyright © 2020 by The Author(s) This is an open access article distributed under the CC BY-NC Attribution 4.0 International license. ASSOCIATE EDITOR: RICHARD D. YE Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 to Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution Uddalak Bharadwaj,1 Moses M. Kasembeli,1 Prema Robinson, and David J. Tweardy Department of Infectious Diseases, Infection Control & Employee Health, Division of Internal Medicine (U.B., M.M.K., P.R., D.J.T.), and Department of Molecular and Cellular Oncology (D.J.T.), University of Texas, MD Anderson Cancer Center, Houston, Texas Abstract. ....................................................................................488 Significance Statement ......................................................................488 I. Molecular and Cellular Biology of Janus Kinase/Signal Transducer and Activator of Transcription 3 Signaling. ..................................................................488 A. Canonical Janus Kinase/Signal Transducer and Activator of Transcription 3 Signaling . 488 1. Janus Kinases .......................................................................488 2. Signal Transducer and Activator of Transcription Proteins . .........................489 Downloaded from 3. Negative Regulation of Canonical Janus Kinase/Signal Transducer and Activator of Transcription 3 Signaling. ............................................................490 4. Post-Translational Modifications of Signal Transducer and Activator of Transcrip- tion 3 . ..............................................................................490 a. Serine 727 phosphorylation . ......................................................490 b. Methylation.......................................................................491 by guest on October 2, 2021 c. Acetylation .......................................................................492 d. Ubiquitination, ISGylation, and SUMOylation .....................................492 B. Noncanonical Signal Transducer and Activator of Transcription 3 Activities . .............492 1. Phosphotyrosine 705–Unphosphorylated Signal Transducer and Activator of Transcription 3.......................................................................492 2. Mitochondrial Signal Transducer and Activator of Transcription 3. ...................493 3. Scaffold Function in Platelets. ......................................................493 4. Signal Transducer and Activator of Transcription 3 in the Endoplasmic Reticulum . 493 II. Biologic Functions of Janus Kinase/Signal Transducer and Activator of Transcription 3 in Basal Conditions ............................................................................494 A. Janus Kinase/Signal Transducer and Activator of Transcription 3 in Hematopoiesis and Immune Cell Function . ............................................................495 1. Granulopoiesis .......................................................................495 2. Platelets .............................................................................495 3. Dendritic Cells .......................................................................498 4. Phagocyte Function ..................................................................499 5. Natural Killer Cell Function..........................................................499 6. B Cells. ..............................................................................499 7. CD41 T Cells ........................................................................499 8. CD81 T Cells ........................................................................500 Address correspondence to: Dr. David J. Tweardy, Department of Infectious Diseases, Infection Control & Employee Health and Department of Molecular Cellular Oncology, University of Texas, MD Anderson Cancer Center, 1400 Pressler Street FCT12.5069, Unit 1463, Houston, TX 77030-3772. E-mail: [email protected] This work was supported by University of Texas for MD Anderson. This work was supported by the National Institutes of Health [Grant 1P50CA221707-01A1]. Baylor College and Medicine, with D.J.T. as inventor, has filed 19 patents covering the use of TTI-101, a small-molecule inhibitor of STAT3 cited in this review. These patents are exclusively licensed to Tvardi Therapeutics, which was founded and is co-owned by D.J.T. 1U.B. and M.M.K. contributed equally to this work. doi.org/10.1124/pr.119.018440. 486 An erratum has been published: /content/72/3/605.full.pdf Targeting JAK/STAT3 Signaling 487 9. Anaphylaxis. ........................................................................500 B. Janus Kinase/Signal Transducer and Activator of Transcription 3 and Metabolism . .......500 1. Lipid Metabolism . ..................................................................500 2. Glucose Metabolism ..................................................................501 III. Functions of Janus Kinase/Signal Transducer and Activator of Transcription 3 in Stress Conditions ..................................................................................501 A. Radiation . ..............................................................................501 B. Oxidative Stress. ........................................................................502 C. Genotoxic Stress. ........................................................................503 D. Cell Senescence . ........................................................................503 E. Autophagy ..............................................................................503 F. Ischemia and Reperfusion Stress. ......................................................504 G. Hyperosmotic Stress . ..................................................................504 IV. Targeting Aberrant Janus Kinase/Signal Transducer and Activator of Transcription 3 Activity in Inflammatory, Fibrotic, Metabolic, and Oncological Diseases . ...................505 A. Strategies to Target Janus Kinases ......................................................505 B. Strategies to Target Signal Transducer and Activator of Transcription 3 ..................505 C. Janus Kinase/Signal Transducer and Activator of Transcription 3 Signaling and Its Targeting in Asthma . ..................................................................506 D. Janus Kinase/Signal Transducer and Activator of Transcription Signaling and Its Targeting in Anaphylaxis ................................................................506 E. Janus Kinase/Signal Transducer and Activator of Transcription 3 Signaling and Its Targeting in Inflammatory Bowel Disease................................................507 F. Janus Kinase/Signal Transducer and Activator of Transcription 3 Signaling and Its Targeting in Cachexia . ..................................................................507 G. Janus Kinase/Signal Transducer and Activator of Transcription 3 Signaling and Its Targeting in Fibrosis . ..................................................................508 H. Janus Kinase/Signal Transducer and Activator of Transcription 3 Signaling and Its Targeting in Metabolic Disorders . ......................................................509 I. Cancer ..................................................................................511 1. Janus Kinases in Cancer . ............................................................511 2. Targeting Janus Kinases in Cancer . ................................................511 3. Signal Transducer and Activator of Transcription 3 in Cancer .........................512 4. Targeting Signal Transducer and Activator of Transcription 3 in Cancer. .............512 a. Antisense oligonucleotide . ......................................................512 b. Signal transducer and activator of transcription 3 decoy oligonucleotides ...........512 c. Small-molecule inhibitors . ......................................................512 i. OPB-31121 . ..................................................................512 ii. OPB-111077..................................................................513 ABBREVIATIONS: AD-HIES, autosomal-dominant hyper-IgE syndrome; AE, adverse event; AgRP, agouti-related protein; Akt, Ak strain transforming; ALD, alcoholic liver disease; C/EBP, CCAAT/enhancer-binding protein; CD, Crohn’s disease; CK2, casein kinase 2; CLL, chronic lymphocytic leukemia; CNS, central nervous system; CRC, colorectal cancer; CSE, cigarette smoke extract; DC, dendritic cell; ECM, extra- cellular matrix; ER, endoplasmic reticulum; ERK, extracellular signal-regulated kinase; ET, essential thrombocythemia; ETC, electron transport chain; FERM, band four-point-one, ezrin, radixin, moesin; GAS, IFN-g activation site; GI, gastrointestinal; GVHD, graft-versus-host disease; HBEC, human bronchial epithelial cell; HCC, hepatocellular carcinoma; HDAC, methyltransferase histone deacetylase; HDM, house dust mite; HNSCC, head and neck squamous cell carcinoma; IBD, inflammatory bowel disease; IFN, interferon; IL, interleukin; iNOS, inducible NO synthase; IP3R3, inositol 1,4,5-trisphosphate receptor, type 3; I/R, ischemia–reperfusion; IR, ionizing radiation; IRS, insulin receptor substrate; ISG, IFN-stimulated gene; JAK, Janus kinase; Jakinib, JAK inhibitor; JH, JAK homology; JNK, c-Jun N-terminal kinase; Keap1, kelch-like ECH-associated protein 1; KO, knockout;