title: 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.affiliation: Cancer Genetics, Digestive Diseases, and Developmental Molecular Biology, Department of Surgery, Georgetown University, Washington, DC 20007, USA.
authors.forename: L
authors.initials: L
authors.lastname: Lin
authors.forename: R
authors.initials: R
authors.lastname: Amin
authors.forename: G I
authors.initials: GI
authors.lastname: Gallicano
authors.forename: E
authors.initials: E
authors.lastname: Glasgow
authors.forename: W
authors.initials: W
authors.lastname: Jogunoori
authors.forename: J M
authors.initials: JM
authors.lastname: Jessup
authors.forename: M
authors.initials: M
authors.lastname: Zasloff
authors.forename: J L
authors.initials: JL
authors.lastname: Marshall
authors.forename: K
authors.initials: K
authors.lastname: Shetty
authors.forename: L
authors.initials: L
authors.lastname: Johnson
authors.forename: L
authors.initials: L
authors.lastname: Mishra
authors.forename: A R
authors.initials: AR
authors.lastname: He
mesh_terms: D000071916:AC133 Antigen; D010131:Aminosalicylic Acid / Q000627:therapeutic use; D000636:Aminosalicylic Acids; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D001557:Benzenesulfonates / Q000627:therapeutic use*; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003114:Colony-Forming Units Assay; D005260:Female; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D007124:Immunoenzyme Techniques; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D010455:Peptides / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000071916:AC133 Antigen; D000636:Aminosalicylic Acids; D015703:Antigens, CD; D001557:Benzenesulfonates; D006023:Glycoproteins; C520337:NSC 74859; C000606023:PROM1 protein, human; D010455:Peptides; C000606024:Prom1 protein, mouse; D050796:STAT3 Transcription Factor; D016212:Transforming Growth Factor beta; D010131:Aminosalicylic Acid