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

Oncogene volume 28, pages 961–972 (2009)Cite this article

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.

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Abbreviations

CSC:

cancer stem cell

β2SP:

embryonic liver fodrin

HCC:

hepatocellular carcinoma

STAT3:

signal transduction and activator of transcription

TGFBR1:

transforming growth factor-β receptor I

TGFBR2:

transforming growth factor-β receptor II

TGF-β:

transforming growth factor-beta

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Acknowledgements

We wish to thank Dr Said M Sebti for helpful discussions on the use of NSC 74859; Dr Joseph Cory for critical review and helpful suggestions with the manuscript; Tiffany Blake, Ed Flores, E Volpe and Sandra Acheampong for excellent technical expertise and manuscript preparation; Mr Carlos Benitez for xenograft production and injection of drugs; and Dr Richard Amdur for statistical analysis. Grant support was provided by NIH R01 CA106614A (LM), NIH R01 DK56111 (LM), NIH R01 CA4285718A (LM), VA Merit Award (LM) (Bao et al.), R Robert and Sally D Funderburg Research Scholar (LM), B Orr Foundation (LM), and NIH P30 CA51008-13 (transgenic shared resource; Cancer Center Support Grant).

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Author notes

  1. L Lin and R Amin: Author contributions: LL and RA contributed equally to this work. ARH, LM, GIG, LJ, KS, RA, and LL designed research; ARH, LL, and RA performed research; GIG, LL, RA, and JJ contributed new reagents/analytical tools; ARH, LL, GIG, JM, KS, MZ, LJ, and LM analyzed data; ARH, EG, LL, RA, GIG, JM, KS, MZ, LJ, and LM wrote the paper.

Authors and Affiliations

  1. Department of Surgery, Cancer Genetics, Digestive Diseases, and Developmental Molecular Biology, Georgetown University, Washington, DC, USA

    L Lin, R Amin, E Glasgow, W Jogunoori, M Zasloff, K Shetty, L Johnson, L Mishra & A R He

  2. Department of Medicine and Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA

    L Lin, E Glasgow, J L Marshall & A R He

  3. Department of Biochemistry and Molecular and Cellular Biology, Georgetown University Medical Center, Washington, DC, USA

    G I Gallicano

  4. Cancer Diagnosis Program, National Cancer Institute, Rockville, MD, USA

    J M Jessup

  5. Department of Surgery, Institute of Transplant Surgery, Georgetown University, Washington, DC, USA

    K Shetty & L Johnson

  6. Department of Veterans Affairs Medical Center, Washington, DC, USA

    L Mishra

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Correspondence to L Mishra or A R He.

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Lin, L., Amin, R., Gallicano, G. et al. The STAT3 inhibitor NSC 74859 is effective in hepatocellular cancers with disrupted TGF-β signaling. Oncogene 28, 961–972 (2009). https://doi.org/10.1038/onc.2008.448

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