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Journal of Thoracic Oncology:
Pathway of the Month

SRC and STAT Pathways

Haura, Eric B. MD

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Address for correspondence: Eric B. Haura, M.D., Thoracic Oncology Program, H. Lee Moffitt Cancer Center and Research Institute, MRC3 East, Room 3056, 12902 Magnolia Drive, Tampa, FL 33612-9497. E-mail: hauraeb@moffitt.usf.edu

Members of the Src family of protein tyrosine kinases (SRC) can link signaling initiated by growth factor, integrin, and cytokine receptors on the surface of cells to their downstream effector signaling cascades (Figure 1).1 Each protein consists of an amino-terminal domain that can be myristoylated, an SH2 and SH3 domain, a tyrosine kinase domain, and a negative regulatory element at the carboxy-terminus. When activated by receptor tyrosine kinases through SH2 binding, SRC is autophosphorylated at tyrosine 419. Phosphorylation of tyrosine 527, however, promotes an intramolecular interaction leading to a closed conformation and inactivation of the catalytic activity of SRC. SRC cooperates with multiple receptor tyrosine kinases to modulate signaling.2 As one example relevant for lung cancer, c-Src cooperates with the epidermal growth factor receptor (EGFR), and Src-kinase activity is required for transformation by EGFR.1–5 Phosphorylation of EGFR by c-Src modulates receptor function and allows for EGF-induced promotion of cell growth, survival, and angiogenesis.6,7

Figure 1
Figure 1
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SRC signaling can result in activation of downstream signaling pathways that control cellular proliferation, survival, invasion and metastasis, and angiogenesis (Figure 1). SRC signaling can allow for enhanced cellular proliferation by up-regulating genes important in cell cycle progression, such as Myc, p21WAF1/CIP1, cyclin D, p27Kip1 and cdc2.8,9 SRC protect cells against apoptosis induced by loss of cell adhesion (anoikis), and PI3K/Akt and Stat3 are key downstream survival cascades regulated by SRC. SRC promotes tumor cell invasion and metastasis by affecting cell adhesion, invasion, and motility.10 c-Src can regulate both focal adhesions and adherens junctions necessary for invasion of tumor cells by activation of downstream focal adhesion kinase (FAK), p130Cas, and paxillin.10 VEGF and HIF1α are downstream targets for c-Src, and small molecule inhibitors of SRC can negatively regulate VEGF and inhibit angiogenesis.11–15

Increased SRC activity is found in human tumors, including lung cancer, resulting from diverse mechanisms including tyrosine phosphatase-mediated dephosphorylation of Tyr 527, increased SRC protein levels, increase in upstream receptor tyrosine kinase activity, or loss of negative regulatory proteins.10,16,17 Small molecule inhibitors of SRC have antitumor properties through negatively regulating cell proliferation, survival, angiogenesis, and invasion.18–20 A number of small-molecule oral SRC tyrosine kinase inhibitors such as dasatinib (BMS-354825), SKI-606, and AZD-0530 have entered early phase clinical trials.

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STAT SIGNALING PATHWAYS

Signal transducers and activators of transcription (STAT) proteins are a family of cytoplasmic transcription factors with similar structure that are activated by tyrosine kinase signals.21–24 STATs are activated when critical tyrosine residues become phosphorylated by protein tyrosine kinases, including membrane-bound growth factor receptors, such as EGFR, and non-receptor tyrosine kinases such as SRC and JAK. Once critical tyrosine residues on STAT proteins become phosphorylated, two monomers dimerize, translocate to the nucleus, and subsequently bind to cognate sequences contained within gene promoters where they cooperate with other transcriptional proteins to regulate gene expression. After activation of STAT-dependent genes, STAT activity is down-regulated through a number of mechanisms. Either gain of function mutations in upstream tyrosine kinases or loss of negative feedback mechanisms can contribute to STAT activation and oncogenesis.

Stat3 and Stat5 regulate basic biological processes important in tumorigenesis, including cell cycle progression, apoptosis, tumor angiogenesis, invasion and metastasis, and tumor cell evasion of the immune system.23 Conversely, Stat1 is thought to play a tumor-suppressor role through anti-growth, pro-death, and enhanced immune recognition of tumor cells.22 Numerous studies have shown constitutive activation of Stat3 and Stat5 in a diverse group to tumors from cancer patients, including lung cancer, and multiple studies have shown that inhibition of Stat3 or Stat5 activation results in growth suppression and apoptosis.18,23,25

Stat3 can up-regulate pro-survival genes such as Bcl-2, Bcl-xL, Mcl-1, survivin, and Akt while Stat3 can repress the pro-death genes TRAIL and p53.23,26,27 Stat3 also regulates genes important in cell-cycle progression, such as Myc and cyclin D1, which act to drive cells through the G1/S cell-cycle check point.8,28 Stat3 has been shown to play an important role in tumor angiogenesis by up-regulating VEGF and HIF1α.29,30 Inhibiting Stat3 in tumor cells increases the expression of pro-inflammatory cytokines that activate innate immune responses in dendritic cells and result in antitumor T-cell responses.31,32 Finally, Stat3 has been implicated in the control of tumor cell invasion and metastasis through direct regulation of matrix metalloproteinase gene products and other genes implicated in tumor cell migration and invasion.33–35

Given the important role of Stat3 in cancer, a large effort is currently underway to develop novel inhibitors of Stat3 as well as Stat5.22,36,37 Indirect approaches include inhibition of hyperactive upstream tyrosine kinase signals from upstream ligand-receptor interactions or aberrant receptor and non-receptor protein tyrosine kinases such as EGFR, SRC, and JAK. A direct approach involves direct targeting of STAT proteins through novel peptides, peptidomimetics, non-peptide analogues, peptide aptamers, platinum (IV) complexes, G-rich oligodeoxynucleotides, decoy oligonucleotides, antisense oligonucleotide, and siRNA approaches (reviewed in37).

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ACKNOWLEDGMENTS

I appreciate the assistance of Lanxi Song in creating the figure and Vicki Lamm for continued administrative assistance.

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REFERENCES

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19. Wei L, Yang Y, Zhang X, Yu Q. Altered regulation of Src upon cell detachment protects human lung adenocarcinoma cells from anoikis. Oncogene 2004;23:9052–9061.

20. Johnson FM, Saigal B, Talpaz M, Donato NJ. Dasatinib (BMS-354825) tyrosine kinase inhibitor suppresses invasion and induces cell cycle arrest and apoptosis of head and neck squamous cell carcinoma and non-small cell lung cancer cells. Clin Cancer Res 2006;11:6924–6932.

21. Darnell JE STATs and gene regulation. Science 1997;277:1630–1635.

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23. Yu H, Jove R. The STATs of cancer: new molecular targets come of age. Nat Rev Cancer 2004;4:97–105.

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25. Haura EB, Zheng Z, Song L, Cantor A, Bepler G. Activated epidermal growth factor receptor-Stat-3 signaling promotes tumor survival in vivo in non-small cell lung cancer. Clin Cancer Res 2006;11:8288–8294.

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27. Park S, Kim D, Kaneko S, et al. Molecular cloning and characterization of the human AKT1 promoter uncovers its up-regulation by the Src/Stat3 pathway. J Biol Chem 2006;280:38932–38941.

28. Bowman T, Broome MA, Sinibaldi D, et al. Stat3-mediated Myc expression is required for Src transformation and PDGF-induced mitogenesis. Proc Natl Acad Sci USA 2001;98:7319–7324.

29. Niu G, Wright KL, Huang M, et al. Constitutive Stat3 activity up-regulates VEGF expression and tumor angiogenesis. Oncogene 2002;21:2000–2008.

30. Xu Q, Briggs J, Park S, et al. Targeting Stat3 blocks both HIF-1 and VEGF expression induced by multiple oncogenic growth signaling pathways. Oncogene 2006;24:5552–5560.

31. Kortylewski M, Kujawski M, Wang T, et al. Inhibiting Stat3 signaling in the hematopoietic system elicits multicomponent antitumor immunity. Nat Med 2006;11:1314–1321.

32. Wang T, Niu G, Kortylewski M, et al. Regulation of the innate and adaptive immune responses by Stat-3 signaling in tumor cells. Nat Med 2004;10:48–54.

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34. Dechow TN, Pedranzini L, Leitch A, et al. Requirement of matrix metalloproteinase-9 for the transformation of human mammary epithelial cells by Stat3-C. Proc Natl Acad Sci USA 2004;101:10602–10607.

35. Xie TX, Wei D, Liu M, et al. Stat3 activation regulates the expression of matrix metalloproteinase-2 and tumor invasion and metastasis. Oncogene 2004;23:3550–3560.

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© 2006International Association for the Study of Lung Cancer

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