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The STAT3 inhibitor NSC 74859 is effective in hepatocellular cancers with disrupted TGF-β signaling
Open accessAbstract
Hepatocellular carcinoma (HCC) is the third leading cause of cancer deaths worldwide, with few effective therapeutic options for advanced disease. At least 40% of HCCs are clonal, potentially arising from STAT3+, NANOG+ and OCT3/4+ liver progenitor/stem cell transformation, along with inactivation of transforming growth factor-beta (TGF-beta) signaling. Here we report significantly greater signal transducer and activator of transcription 3 (STAT3) and tyrosine phosphorylated STAT3 in human HCC tissues (P<0.0030 and P<0.0455, respectively) than in human normal liver. Further, in HCC cells with loss of response to TGF-beta, NSC 74859, a STAT3-specific inhibitor, markedly suppresses growth. In contrast, CD133(+) status did not affect the response to STAT3 inhibition: both CD133(+) Huh-7 cells and CD133(-) Huh-7 cells are equally sensitive to NSC 74859 treatment and STAT3 inhibition, with an IC(50) of 100 muM. Thus, the TGF-beta/beta2 spectrin (beta2SP) pathway may reflect a more functional 'stem/progenitor' state than CD133. Furthermore, NSC 74859 treatment of Huh-7 xenografts in nude mice significantly retarded tumor growth, with an effective dose of only 5 mg/kg. Moreover, NSC 74859 inhibited tyrosine phosphorylation of STAT3 in HCC cells in vivo. We conclude that inhibiting interleukin 6 (IL6)/STAT3 in HCCs with inactivation of the TGF-beta/beta2SP pathway is an effective approach in management of HCCs. Thus, IL6/STAT3, a major signaling pathway in HCC stem cell renewal and proliferation, can provide a novel approach to the treatment of specific HCCs.
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Impaired immune and acute-phase responses in interleukin-6-deficient mice
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Serine Phosphorylation and Negative Regulation of Stat3 by JNK
Lim, C. P., & Cao, X. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.43.31055 · Cited by 225
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Tackling the cancer stem cells — what challenges do they pose?
Pattabiraman, D. R., & Weinberg, R. A. (2014) · Nature Reviews Drug Discovery · doi:10.1038/nrd4253 · Cited by 990
Lee, T. K. W., Castilho, A., Cheung, V. C. H., Tang, K. H., Ma, S., & Ng, I. O. L. (2011) · Cell Stem Cell · doi:10.1016/j.stem.2011.06.005 · Cited by 586
Stat3 and MMP7 Contribute to Pancreatic Ductal Adenocarcinoma Initiation and Progression
Fukuda, A., Wang, S. C., Morris, J. P., Folias, A. E., Liou, A., Kim, G. E., Akira, S., Boucher, K. M., Firpo, M. A., Mulvihill, S. J., et al. (2011) · Cancer Cell · doi:10.1016/j.ccr.2011.03.002 · Cited by 521
He, G., Yu, G.-Y., Temkin, V., Ogata, H., Kuntzen, C., Sakurai, T., Sieghart, W., Peck-Radosavljevic, M., Leffert, H. L., & Karin, M. (2010) · Cancer Cell · doi:10.1016/j.ccr.2009.12.048 · Cited by 427
Metadata
- Authors
- Lin, L., Amin, R., Gallicano, G. I., Glasgow, E., Jogunoori, W., Jessup, J. M., Zasloff, M., Marshall, J. L., Shetty, K., Johnson, L., Mishra, L., & He, A. R.
- Venue
- Oncogene
- Published
- 2009-01-12
- Volume
- 28
- Issue
- 7
- Pages
- 961-972
- ISSN
- 0950-9232 (ISSN-L)
- 1476-5594
- OpenAlex
- W2129788206
- Cited by
- 207
- References
- 3
- FWCI
- 10.89
- Type
- journal article
- Language
- en
- Open access
- hybrid
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- CoChat. (2026). Citation check: The STAT3 inhibitor NSC 74859 is effective in hepatocellular cancers with disrupted TGF-β signaling. https://app.cochat.ai/papers/10.1038/onc.2008.448
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- Lin, L., Amin, R., Gallicano, G. I., Glasgow, E., Jogunoori, W., Jessup, J. M., Zasloff, M., Marshall, J. L., Shetty, K., Johnson, L., Mishra, L., & He, A. R. (2009). The STAT3 inhibitor NSC 74859 is effective in hepatocellular cancers with disrupted TGF-β signaling. Oncogene. https://doi.org/10.1038/onc.2008.448
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