Inhibition of Stat3 activity by YC-1 enhances chemo-sensitivity in hepatocellular carcinoma.

Abstract

The present study investigated the effect of YC-1, a novel anti-cancer agent, on the chemo-sensitivity of hepatocellular carcinoma (HCC). YC-1 was administered with chemo-cytotoxic drug, cisplatin, both in vitro and in vivo. YC-1 alone downregulated the expression of phosphorylated form of signal transducers and activators of transcription 3 (P-Stat3[705]), a key mediator in chemo-resistance. When combined with cisplatin, YC-1 further promoted tumor cell apoptosis, decreased the expression of P-Stat3(705), Bcl-xL, CyclinD1 and survivin, and induced the cleavage of caspase 9 and PARP. Overexpression of Stat3 reversed YC-1 induced cell death. YC-1 inhibited Stat3 activity by enhancing the polyubiquitination of P-Stat3(705) induced by cisplatin. In the in vivo setting, YC-1 combined with cisplatin remarkably suppressed tumor growth in a HCC xenograft model, and this effect was also accompanied by YC-1 mediated downregulation of P-Stat3(705), Bcl-xL, Cyclin D1 and survivin, and induction of cleaved caspase 9 and PARP in the tumor tissues. In conclusion, the present study demonstrated a novel anti-cancer effect of YC-1 in enhancing chemo-sensitivity of HCC cells to cisplatin through a Stat3 dependent manner. This finding provides insight into design of a new therapeutic strategy to improve efficacy of chemotherapy in HCC patients.

• Authors: Chi Keung Lau, Zhen Fan Yang, Shuk Pik Lam, Chi Tat Lam, Patricia Ngai, Ka Ho Tam, Ronnie Tung-Ping Poon, Sheung Tat Fan
• Journal: Cancer biology & therapy (Cancer Biol Ther) Vol. 6 Issue 12 Pg. 1900-7 (Dec 2007) ISSN: 1555-8576 [Electronic] United States
• PMID: 18059167 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• BCL2L1 protein, human
• BIRC5 protein, human
• Cyclin D
• Cyclins
• Indazoles
• Inhibitor of Apoptosis Proteins
• Microtubule-Associated Proteins
• Neoplasm Proteins
• STAT3 Transcription Factor
• STAT3 protein, human
• Survivin
• bcl-X Protein
• 3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole
• PARP1 protein, human
• Poly (ADP-Ribose) Polymerase-1
• Poly(ADP-ribose) Polymerases
• CASP9 protein, human
• Caspase 9
• Cisplatin

Topics

• Animals
• Antineoplastic Agents (pharmacology, therapeutic use)
• Apoptosis (drug effects)
• Carcinoma, Hepatocellular (drug therapy, metabolism, pathology)
• Caspase 9 (biosynthesis, genetics)
• Cell Line, Tumor (drug effects, metabolism)
• Cisplatin (pharmacology)
• Cyclin D
• Cyclins (biosynthesis, genetics)
• Drug Resistance, Neoplasm (drug effects)
• Drug Synergism
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Indazoles (pharmacology, therapeutic use)
• Inhibitor of Apoptosis Proteins
• Liver Neoplasms (drug therapy, metabolism, pathology)
• Liver Neoplasms, Experimental (drug therapy, metabolism, pathology)
• Mice
• Microtubule-Associated Proteins (biosynthesis, genetics)
• Neoplasm Proteins (antagonists & inhibitors, biosynthesis, genetics)
• Poly (ADP-Ribose) Polymerase-1
• Poly(ADP-ribose) Polymerases (biosynthesis, genetics)
• Protein Processing, Post-Translational (drug effects)
• STAT3 Transcription Factor (antagonists & inhibitors, metabolism)
• Survivin
• Ubiquitination (drug effects)
• Xenograft Model Antitumor Assays
• bcl-X Protein (biosynthesis, genetics)