Warren S.-L. Liao, Ph.D.

The induction of acute-phase gene expression in the liver during inflammation involves a complex chain of events. Local reaction to tissue injury leads to the production of cytokines, such as interleukin-1 (IL-1), IL-6, and tumor necrosis factor (TNF). These circulating factors then transmit their signals to target cells, triggering the activation of transcription factors, such as NFKB and STAT3, and the induction of gene expression. We have previously studied the molecular mechanisms governing the transcriptional regulation of these genes. More recently, we have focused on the intracellular signaling mechanisms elicited by these cytokines and how the aberrant regulation may contribute to cancer. In addition, we are developing a specific STAT3 inhibitor with the goal to use it as a therapeutic agent to treat certain types of cancer.

In dissecting IL-1 and TNF signaling mechanisms, we found that PI-3 kinase and MEKK3 play major roles in mediating NFKB activation. Inhibition of PI-3 kinase completely blocks NFKB activation. Furthermore, PI-3 kinase cooperates with other IL-1- and TNF-inducible signals to synergistically activate NFKB. Similarly, IL-1 and TNF fail to activate NFKB in MEKK3(-/-) cells, suggesting their importance in transducing cytokine signals. Consistent with its importance in NFKB activation, we found that nearly 50% of breast and ovarian cancers have elevated MEKK3, which correlated with elevated NFKB activity. Moreover, cells with high MEKK3 are more resistant to drug-induced apoptosis. Future studies will examine the role of MEKK3 in cancer development and resistance to apoptosis.

Our other project deals with the development of a novel drug to inhibit the activity of STAT3 transcription factor in cancer cells. STAT3 regulates a wide variety of genes involved in cell proliferation and cell survival. In response to cytokines or growth factors, STAT3 is rapidly tyrosine phosphorylated and dimerized. This dimerization is absolutely required for STAT3 activation. In many human cancers, STAT3 is constitutively activated, resulting in dysregulation of downstream target genes involved in cell cycle, cell survival/apoptosis, and oncogenesis. Thus, constitutive activation of STAT3 leads to profound alterations in cellular behavior and contribute to cell transformation. As such, STAT3 signaling pathway provides an excellent target for effective therapeutic intervention in human cancers. Our goal in this study is to develop novel small phosphopeptides as specific inhibitors of STAT3 dimerization and activation. We have tested a few first-generation peptide inhibitors and found them to be effective inhibitors. Future studies will aim to characterize and assess the effectiveness of these phosphopeptides in inhibiting STAT3 function and to examine their ability to inhibit cancer cell proliferation and to induce apoptosis.

Recent publications

Lu, Z., Luo, R.Z., Peng, H., Huang, M., Nishimoto, A., Hunt, K.K., Helin, K., Liao, W.S-L., and Yu, Y. (2005) E2F-HDAC Complexes Negatively Regulate the Tumor Suppressor Gene ARHI in Breast Cancer. Oncogene, in press
Nishimoto, A., Yu, Y., Lu, Z., Mao, X., Ren, Z., Watowich, S.S., Mills, G.B., Liao, W.S-L., Chen, X., Bast, R.C., Jr., and Luo, R.Z. (2005) A Ras Homologue Member I Directly Inhibits Signal Transducers and Activators of Transcription 3 Translocation and Activity in Human Breast and Ovarian Cancer Cells. Cancer Res.65:6701–6710.
Reddy, S.A.G., Lin, Y-F., Huang, H.J., Samanta, A.K., and Liao, W.S.L. (2004) The IL-1 Receptor Accessory Protein is Essential for PI 3-Kinase Recruitment and Activation. Biochem. Biophy. Res. Com. 316:1022–1028.
Samanta, A.K., Huang, H.J., Bast, R.C., Jr., and Liao, W.S.L. (2004) Overexpression of MEKK3 Confers Resistance to Apoptosis through Activation of NFB. J. Biol. Chem. 279:7576–7583.
Wang, H., Wang, H., Shen, W., Huang, H., Hu, L., Ramdas, L. Zhou, Y.-H., Liao, W.S.L., Fuller, G.N., and Zhang, W. (2003) Insulin-like Growth Factor Binding Protein 2 Enhances Glioblastoma Invasion by Activating Invasion-Enhancing Genes. Cancer Res. 63:4315–4321.
Luo, R.Z., Fang, X., Marquez, R., Liu, S.Y., Mills, G.B., Liao, W.S.L., Yu, Y., and Bast, R.C., Jr. (2003) ARHI is a Ras-related Small G-protein with a Novel N-terminal Extension that Inhibits Growth of Ovarian and Breast Cancers. Oncogene 22:2897–2909.
Yang, J., Lin, Y., Guo, Z., Cheng, J., Huang, H., Liao, W.S.L., Chen, Z,. Liu, Z., and Su, B. (2001) Disruption of MEKK3 Defines its Crucial Role in TNF-Induced NFKB Activation. Nature Immunology. 2:620-624.
Luo, R.Z., Peng, H., Xu, F., Bao, J., Pang, Y., Pershad, R., Issa, J.P., Liao, W.S.L., Bast, R.C., Jr., and Yu, Y. (2001) Genomic Structure and Promoter Characterization of an Imprinted Tumor Suppressor Gene ARHI. Biochim Biophys Acta. 1519:216–222.
Wang, H. and Liao, W.S.L. (2001) Functional Analysis of a Minimal Mouse Serum Amyloid A3 Promoter in Transgenic Mice. Amyloid, 8:250–256.
Ren Y, Liao WS (2001) Transcription factor AP-2 functions as a repressor that contributes to the liver-specific expression of serum amyloid A1 gene. J Biol Chem 276, 17770–17778.
Yang, J., Lin, Y., Guo, Z., Cheng, J., Huang, H., Liao, W.S.L., Chen, Z,. Liu, Z., and Su, B. (2001) The Essential Role of MEKK3 in TNF-Induced NFKB Activation. Nature Immunol. 2:620–624.
Bing Z, Huang JH, Liao WS (2000) NFkappaB interacts with serum amyloid A3 enhancer factor to synergistically activate mouse serum amyloid A3 gene transcription. J Biol Chem 275, 31616–31623.
Reddy SA, Huang JH, Liao WS (2000) Phosphatidylinositol 3-kinase as a mediator of TNF-induced NFKB activation. J Immunol 164, 1355–1363.
Bing, Z., Reddy, S.A.G., Ren, Y. and Liao, W.S.-L. (1999) Purification and Characterization of Serum Amyloid A Enhancer Factor. J. Biol. Chem. 274:24649–24656.
Reddy, S.A.G., Huang, J.H., and Liao, W.S.L. (1997) Phosphatidylinositol-3 Kinase in Interleukin-1 signaling: Physical Interaction with the IL-1 Receptor and Requirement in NFKB and AP-1 Activation. J. Biol. Chem. 272: 29167–29173.