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

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-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.

• Authors: 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
• Journal: Oncogene (Oncogene) Vol. 28 Issue 7 Pg. 961-72 (Feb 19 2009) ISSN: 1476-5594 [Electronic] England
• PMID: 19137011 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• AC133 Antigen
• Aminosalicylic Acids
• Antigens, CD
• Benzenesulfonates
• Glycoproteins
• NSC 74859
• PROM1 protein, human
• Peptides
• Prom1 protein, mouse
• STAT3 Transcription Factor
• Transforming Growth Factor beta
• Aminosalicylic Acid

Topics

• AC133 Antigen
• Aminosalicylic Acid (therapeutic use)
• Aminosalicylic Acids
• Animals
• Antigens, CD (metabolism)
• Apoptosis (drug effects)
• Benzenesulfonates (therapeutic use)
• Blotting, Western
• Carcinoma, Hepatocellular (drug therapy, metabolism, pathology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Colony-Forming Units Assay
• Female
• Glycoproteins (metabolism)
• Humans
• Immunoenzyme Techniques
• Liver Neoplasms (drug therapy, metabolism, pathology)
• Mice
• Mice, Nude
• Peptides (metabolism)
• Phosphorylation (drug effects)
• STAT3 Transcription Factor (antagonists & inhibitors, metabolism)
• Transforming Growth Factor beta (genetics, metabolism)
• Xenograft Model Antitumor Assays