STAT proteins as novel targets for cancer drug discovery.
Signal transducer and activator of transcription (STAT) proteins are latent cytoplasmic transcription factors that were discovered in the context of cytokine and growth factor signalling. Normal STAT signalling is tightly controlled with finite kinetics, which is in keeping with standard cellular responses. However, persistent STAT activation has also been observed and is frequently associated with malignant transformation. Constitutive activation of STAT proteins, notably of Stat3 and Stat5, is detected in many human tumour cells and cells transformed by oncoproteins that activate tyrosine kinase signalling pathways. It is well-established that constitutively active Stat3 is one of the molecular abnormalities that has a causal role in oncogenesis. Aberrant Stat3 promotes uncontrolled growth and survival through dysregulation of gene expression, including cyclin D1, c-Myc, Bcl-xL, Mcl-1 and survivin genes, and thereby contributes to oncogenesis. Moreover, recent studies reveal that persistently active Stat3 induces tumour angiogenesis by upregulation of vascular endothelial growth factor induction, and modulates immune functions in favour of tumour immune evasion. Overall, studies have validated Stat3 as a novel target for cancer therapy, and hence provided the rationale for developing small-molecule Stat3 inhibitors. This review will discuss current evidence for the critical role of aberrant STAT signalling in malignant transformation, and examine the validity as well as the therapeutic potential of Stat3 as a cancer target. An update on the efforts to develop novel Stat3 inhibitors for therapeutic application will also be provided.
Turkson
James
J
Molecular Oncology Program, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, SRB 22214, Tampa, FL 33612, USA. turksonj@moffitt.usf.edu
D020533:Angiogenesis Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000502:physiology; D015195:Drug Design; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008297:Male; D008894:Milk Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D008954:Models, Biological; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics / Q000502:physiology; D009369:Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000235:genetics; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000235:genetics; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D050794:STAT1 Transcription Factor; D050795:STAT2 Transcription Factor; D050796:STAT3 Transcription Factor; D050797:STAT4 Transcription Factor; D050799:STAT5 Transcription Factor; D050800:STAT6 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013329:Structure-Activity Relationship; D015534:Trans-Activators / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000502:physiology
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D008894:Milk Proteins; D009363:Neoplasm Proteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050795:STAT2 Transcription Factor; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D050797:STAT4 Transcription Factor; C494090:STAT4 protein, human; D050799:STAT5 Transcription Factor; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; D015534:Trans-Activators; D011494:Protein Kinases