The STAT3 inhibitor NSC 74859 is effective in hepatocellular cancers with disrupted TGF-β signaling

L. Lin, R. Amin, G. I. Gallicano, E. Glasgow, W. Jogunoori, J. M. Jessup, M. Zasloff, J. L. Marshall, K. Shetty, L. Johnson, L. Mishra, A. R. He

Research output: Contribution to journalArticle

Abstract

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-β) 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-β, 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 IC50 of 100 μM. Thus, the TGF-β/beta2 spectrin (β2SP) 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-β/β2SP 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.

Original languageEnglish (US)
Pages (from-to)961-972
Number of pages12
JournalOncogene
Volume28
Issue number7
DOIs
StatePublished - Feb 19 2009

Keywords

  • Hepatocellular carcinoma
  • IL6
  • STAT3
  • Stem cell
  • TGF-β
  • β2SP

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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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, 28(7), 961-972. https://doi.org/10.1038/onc.2008.448