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+ 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
Externally publishedYes

Fingerprint

NSC 74859
STAT3 Transcription Factor
Liver Neoplasms
Transforming Growth Factor beta
Hepatocellular Carcinoma
Interleukin-6
Stem Cells
Transforming Growth Factor beta2
Spectrin
Heterografts
Nude Mice
Inhibitory Concentration 50
Tyrosine

Keywords

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

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Lin, L., Amin, R., Gallicano, G. I., Glasgow, E., Jogunoori, W., Jessup, J. M., ... 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

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

In: Oncogene, Vol. 28, No. 7, 19.02.2009, p. 961-972.

Research output: Contribution to journalArticle

Lin, L, Amin, R, Gallicano, GI, Glasgow, E, Jogunoori, W, Jessup, JM, Zasloff, M, Marshall, JL, Shetty, K, Johnson, L, Mishra, L & He, AR 2009, 'The STAT3 inhibitor NSC 74859 is effective in hepatocellular cancers with disrupted TGF-β signaling', Oncogene, vol. 28, no. 7, pp. 961-972. https://doi.org/10.1038/onc.2008.448
Lin L, Amin R, Gallicano GI, Glasgow E, Jogunoori W, Jessup JM et al. The STAT3 inhibitor NSC 74859 is effective in hepatocellular cancers with disrupted TGF-β signaling. Oncogene. 2009 Feb 19;28(7):961-972. https://doi.org/10.1038/onc.2008.448
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. / The STAT3 inhibitor NSC 74859 is effective in hepatocellular cancers with disrupted TGF-β signaling. In: Oncogene. 2009 ; Vol. 28, No. 7. pp. 961-972.
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