Name: Summary of the probe development efforts to identify dual inhibitors of signal transducer and activator of transcription 3 (STAT3) and nuclear factor NF-kappa-B (NF-kB). ..more
Table of Contents
Targets
| Sequence: STAT3 [Homo sapiens] Protein Family: Src homology 2 (SH2) domain Gene:STAT3 Related Protein 3D Structures |
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Depositor Specified Assays
Description:
Source (MLSCN Center Name): The Scripps Research Institute Molecular Screening Center
Center Affiliation: The Scripps Research Institute (TSRI)
Assay Provider: David Frank, Dana Farber Cancer Institute
Network: Molecular Library Screening Center Network (MLSCN)
Grant Proposal Number: 1 X01 MH079826-01
Grant Proposal PI: David Frank, Dana Farber Cancer Institute
External Assay ID: STAT3-NFKB_INH_SUMMARY
Name: Summary of the probe development efforts to identify dual inhibitors of signal transducer and activator of transcription 3 (STAT3) and nuclear factor NF-kappa-B (NF-kB).
Description:
In recent years, much evidence has indicated that members of the signal transducer and activator of transcription (STAT) family of transcription factors: (1) malfunction commonly in cancer cells, (2) are necessary for the continued maintenance of the cancer, and (3) are dispensable in normal cells. Studies show that STAT3 is activated in breast and prostate cancers, and that STAT3 inhibition using RNA interference or a dominant negative leads to reduced cell proliferation, survival, and wound healing (1-5). In addition, the Nuclear Factor-kB (NF-kB) has been recognized as a major pathway for both inflammation-induced carcinogenesis and anti-tumor immunity. Intriguingly, STAT3 and NF-kB are frequently persistently activated in the same tumor cells, and in tumor-associated myeloid cells (6, 7). In such contexts, both transcription factors have crucial and integrated roles in inflammatory responses that promote cancer development and growth. Recently, several studies have suggested that combined STAT3/NF-kB inhibition would be beneficial to tumor prevention and therapy (8-12).
In the work we have done so far in developing STAT3 inhibitory probes, a consistent finding has been that compounds that selectively inhibit STAT3 frequently lead to a reciprocal increase in NF-kB activity. This likely reflects loss of expression of negative feedback regulators, and we are currently working to define the mechanism for this. In addition, since NF-kB target genes promote survival and proliferation, this effect may diminish the anti-neoplastic efficacy of a pure STAT3 inhibitor. Thus, a dual STAT3/NF-kB inhibitor holds the promise of being a much more effective anti-cancer agent.
Summary of Probe Development Effort:
This probe development effort is focused on the identification of dual STAT3/NF-kB inhibitors. All AIDs that contain results associated with this project can be found in the "Related Bioassays" section of this Summary AID.
References:
1. Alvarez, J.V., P.G. Febbo, S. Ramaswamy, M. Loda, A. Richardson, and D.A. Frank, Identification of a genetic signature of activated signal transducer and activator of transcription 3 in human tumors. Cancer Res, 2005. 65(12): p. 5054-62.
2. Levy, D.E. and J.E. Darnell, Jr., Stats: transcriptional control and biological impact. Nat Rev Mol Cell Biol, 2002. 3(9): p. 651-62.
3. Takeda, K., T. Kaisho, N. Yoshida, J. Takeda, T. Kishimoto, and S. Akira, Stat3 activation is responsible for IL-6-dependent T cell proliferation through preventing apoptosis: generation and characterization of T cell-specific Stat3-deficient mice. J Immunol, 1998. 161(9): p. 4652-60.
4. Nelson, E.A., S.R. Walker, A. Kepich, L.B. Gashin, T. Hideshima, H. Ikeda, D. Chauhan, K.C. Anderson, and D.A. Frank, Nifuroxazide inhibits survival of multiple myeloma cells by directly inhibiting STAT3. Blood, 2008. 112(13): p. 5095-102.
5. Walker, S.R., E.A. Nelson, and D.A. Frank, STAT5 represses BCL6 expression by binding to a regulatory region frequently mutated in lymphomas. Oncogene, 2007. 26(2): p. 224-33.
6. Yu, H., D. Pardoll, and R. Jove, STATs in cancer inflammation and immunity: a leading role for STAT3. Nat Rev Cancer, 2009. 9(11): p. 798-809.
7. Grivennikov, S.I. and M. Karin, Dangerous liaisons: STAT3 and NF-kappaB collaboration and crosstalk in cancer. Cytokine Growth Factor Rev, 2010. 21(1): p. 11-9.
8. Greten, F.R., C.K. Weber, T.F. Greten, G. Schneider, M. Wagner, G. Adler, and R.M. Schmid, Stat3 and NF-kappaB activation prevents apoptosis in pancreatic carcinogenesis. Gastroenterology, 2002. 123(6): p. 2052-63.
9. Lam, L.T., G. Wright, R.E. Davis, G. Lenz, P. Farinha, L. Dang, J.W. Chan, A. Rosenwald, R.D. Gascoyne, and L.M. Staudt, Cooperative signaling through the signal transducer and activator of transcription 3 and nuclear factor-{kappa}B pathways in subtypes of diffuse large B-cell lymphoma. Blood, 2008. 111(7): p. 3701-13.
10. Lee, T.L., J. Yeh, J. Friedman, B. Yan, X. Yang, N.T. Yeh, C. Van Waes, and Z. Chen, A signal network involving coactivated NF-kappaB and STAT3 and altered p53 modulates BAX/BCL-XL expression and promotes cell survival of head and neck squamous cell carcinomas. Int J Cancer, 2008. 122(9): p. 1987-98.
11. Malara, N., D. Foca, F. Casadonte, M.F. Sesto, L. Macrina, L. Santoro, M. Scaramuzzino, R. Terracciano, and R. Savino, Simultaneous inhibition of the constitutively activated nuclear factor kappaB and of the interleukin-6 pathways is necessary and sufficient to completely overcome apoptosis resistance of human U266 myeloma cells. Cell Cycle, 2008. 7(20): p. 3235-45.
12. Lee, H., A. Herrmann, J.H. Deng, M. Kujawski, G. Niu, Z. Li, S. Forman, R. Jove, D.M. Pardoll, and H. Yu, Persistently activated Stat3 maintains constitutive NF-kappaB activity in tumors. Cancer Cell, 2009. 15(4): p. 283-93.
Keywords:
Summary, Summary AID, STAT3, NFkB, Ricerca, signal transducer and activator of transcription 3, acute-phase response factor, APRF, inhibitor, inhibition, transcription factor, luciferase, luminescence, assay, Scripps, Scripps Florida, Scripps Research Institute Molecular Screening Center, SRIMSC, Molecular Libraries Probe Production Centers Network, MLPCN.
Center Affiliation: The Scripps Research Institute (TSRI)
Assay Provider: David Frank, Dana Farber Cancer Institute
Network: Molecular Library Screening Center Network (MLSCN)
Grant Proposal Number: 1 X01 MH079826-01
Grant Proposal PI: David Frank, Dana Farber Cancer Institute
External Assay ID: STAT3-NFKB_INH_SUMMARY
Name: Summary of the probe development efforts to identify dual inhibitors of signal transducer and activator of transcription 3 (STAT3) and nuclear factor NF-kappa-B (NF-kB).
Description:
In recent years, much evidence has indicated that members of the signal transducer and activator of transcription (STAT) family of transcription factors: (1) malfunction commonly in cancer cells, (2) are necessary for the continued maintenance of the cancer, and (3) are dispensable in normal cells. Studies show that STAT3 is activated in breast and prostate cancers, and that STAT3 inhibition using RNA interference or a dominant negative leads to reduced cell proliferation, survival, and wound healing (1-5). In addition, the Nuclear Factor-kB (NF-kB) has been recognized as a major pathway for both inflammation-induced carcinogenesis and anti-tumor immunity. Intriguingly, STAT3 and NF-kB are frequently persistently activated in the same tumor cells, and in tumor-associated myeloid cells (6, 7). In such contexts, both transcription factors have crucial and integrated roles in inflammatory responses that promote cancer development and growth. Recently, several studies have suggested that combined STAT3/NF-kB inhibition would be beneficial to tumor prevention and therapy (8-12).
In the work we have done so far in developing STAT3 inhibitory probes, a consistent finding has been that compounds that selectively inhibit STAT3 frequently lead to a reciprocal increase in NF-kB activity. This likely reflects loss of expression of negative feedback regulators, and we are currently working to define the mechanism for this. In addition, since NF-kB target genes promote survival and proliferation, this effect may diminish the anti-neoplastic efficacy of a pure STAT3 inhibitor. Thus, a dual STAT3/NF-kB inhibitor holds the promise of being a much more effective anti-cancer agent.
Summary of Probe Development Effort:
This probe development effort is focused on the identification of dual STAT3/NF-kB inhibitors. All AIDs that contain results associated with this project can be found in the "Related Bioassays" section of this Summary AID.
References:
1. Alvarez, J.V., P.G. Febbo, S. Ramaswamy, M. Loda, A. Richardson, and D.A. Frank, Identification of a genetic signature of activated signal transducer and activator of transcription 3 in human tumors. Cancer Res, 2005. 65(12): p. 5054-62.
2. Levy, D.E. and J.E. Darnell, Jr., Stats: transcriptional control and biological impact. Nat Rev Mol Cell Biol, 2002. 3(9): p. 651-62.
3. Takeda, K., T. Kaisho, N. Yoshida, J. Takeda, T. Kishimoto, and S. Akira, Stat3 activation is responsible for IL-6-dependent T cell proliferation through preventing apoptosis: generation and characterization of T cell-specific Stat3-deficient mice. J Immunol, 1998. 161(9): p. 4652-60.
4. Nelson, E.A., S.R. Walker, A. Kepich, L.B. Gashin, T. Hideshima, H. Ikeda, D. Chauhan, K.C. Anderson, and D.A. Frank, Nifuroxazide inhibits survival of multiple myeloma cells by directly inhibiting STAT3. Blood, 2008. 112(13): p. 5095-102.
5. Walker, S.R., E.A. Nelson, and D.A. Frank, STAT5 represses BCL6 expression by binding to a regulatory region frequently mutated in lymphomas. Oncogene, 2007. 26(2): p. 224-33.
6. Yu, H., D. Pardoll, and R. Jove, STATs in cancer inflammation and immunity: a leading role for STAT3. Nat Rev Cancer, 2009. 9(11): p. 798-809.
7. Grivennikov, S.I. and M. Karin, Dangerous liaisons: STAT3 and NF-kappaB collaboration and crosstalk in cancer. Cytokine Growth Factor Rev, 2010. 21(1): p. 11-9.
8. Greten, F.R., C.K. Weber, T.F. Greten, G. Schneider, M. Wagner, G. Adler, and R.M. Schmid, Stat3 and NF-kappaB activation prevents apoptosis in pancreatic carcinogenesis. Gastroenterology, 2002. 123(6): p. 2052-63.
9. Lam, L.T., G. Wright, R.E. Davis, G. Lenz, P. Farinha, L. Dang, J.W. Chan, A. Rosenwald, R.D. Gascoyne, and L.M. Staudt, Cooperative signaling through the signal transducer and activator of transcription 3 and nuclear factor-{kappa}B pathways in subtypes of diffuse large B-cell lymphoma. Blood, 2008. 111(7): p. 3701-13.
10. Lee, T.L., J. Yeh, J. Friedman, B. Yan, X. Yang, N.T. Yeh, C. Van Waes, and Z. Chen, A signal network involving coactivated NF-kappaB and STAT3 and altered p53 modulates BAX/BCL-XL expression and promotes cell survival of head and neck squamous cell carcinomas. Int J Cancer, 2008. 122(9): p. 1987-98.
11. Malara, N., D. Foca, F. Casadonte, M.F. Sesto, L. Macrina, L. Santoro, M. Scaramuzzino, R. Terracciano, and R. Savino, Simultaneous inhibition of the constitutively activated nuclear factor kappaB and of the interleukin-6 pathways is necessary and sufficient to completely overcome apoptosis resistance of human U266 myeloma cells. Cell Cycle, 2008. 7(20): p. 3235-45.
12. Lee, H., A. Herrmann, J.H. Deng, M. Kujawski, G. Niu, Z. Li, S. Forman, R. Jove, D.M. Pardoll, and H. Yu, Persistently activated Stat3 maintains constitutive NF-kappaB activity in tumors. Cancer Cell, 2009. 15(4): p. 283-93.
Keywords:
Summary, Summary AID, STAT3, NFkB, Ricerca, signal transducer and activator of transcription 3, acute-phase response factor, APRF, inhibitor, inhibition, transcription factor, luciferase, luminescence, assay, Scripps, Scripps Florida, Scripps Research Institute Molecular Screening Center, SRIMSC, Molecular Libraries Probe Production Centers Network, MLPCN.
Additional Information
Grant Number: 1 X01 MH079826-01
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