Inhibition of the Signal Transducers and Activators of Transcription (STAT) 3 Signalling Pathway by AG490 in Laryngeal Carcinoma Cells

Abstract

Signal transducers and activators of transcription (STAT) are important in the development of laryngeal carcinomas and are potential novel molecular targets for therapy to improve survival of patients with this cancer. This study was designed to investigate the influence of the janus activated kinase (JAK)/STAT inhibitor AG490 on proliferation and apoptosis of Hep-2 human laryngeal cancer cells and whether there was any inhibition by AG490 of the JAK/STAT3 signalling pathway. AG490 inhibited cell proliferation in dose-and time-dependent manners and induced apoptosis in Hep-2 cells, with the number of apoptotic cells increasing with time. AG490 inhibited G₁ to S cell cycle transition and induced G₁ cell cycle arrest as well as significantly down-regulating STAT3, phosphorylated STAT3 and survivin in Hep-2 cells. This study showed that AG490 significantly inhibited proliferation and induced apoptosis of laryngeal carcinoma cells through down-regulation of STAT3 and survivin, suggesting a potential target for laryngeal carcinoma treatment.

Keywords

Laryngeal neoplasm Signal transducers and activators of transcription 3 (STAT3)Survivin Apoptosis Janus activated kinase (JAK) inhibitor

References

Klampfer

: Signal transducers and activators of transcription (STATs): Novel targets of chemopreventive and chemotherapeutic drugs. Curr Cancer Drug Targets 2006; 6: 107–121.

Chen

Hsieh

Lieblein

: Stat3 activation in human endometrial and cervical cancers. Br J Cancer 2007; 96: 591–599.

Kanda

Seno

Konda

: STAT3 is constitutively activated and supports cell survival in association with survivin expression in gastric cancer cells. Oncogene 2004; 23: 4921–4929.

Alas

Bonavida

: Inhibition of constitutive STAT3 activity sensitizes resistant non-Hodgkin's lymphoma and multiple myeloma to chemotherapeutic drug-mediated apoptosis. Clin Cancer Res 2003; 9: 316–326.

Jing

Tweardy

: Targeting STAT3 in cancer therapy. Anticancer Drugs 2005; 16: 601–607.

Gao

Wen

: Inhibition of STAT3 expression by siRNA suppresses growth and induces apoptosis in laryngeal cancer cells. Acta Pharmacol Sin 2005; 26: 377–383.

Niu

Wright

Huang

: Constitutive STAT3 activity up-regulates VEGF expression and tumor angiogenesis. Oncogene 2002; 21: 2000–2008.

Alas

Bonavida

: Rituximab inactivates signal transducer and activation of transcription 3 (STAT3) activity in B-non-Hodgkin's lymphoma through inhibition of the interleukin 10 autocrine/paracrine loop and results in down-regulation of Bcl-2 and sensitization to cytotoxic drugs. Cancer Res 2001; 61: 5137–5144.

Dauer

Ferraro

Song

: STAT3 regulates genes common to both wound healing and cancer. Oncogene 2005; 24: 3397–3408.

10.

Epling-Burnette

Liu

Catlett-Falcone

: Inhibition of STAT3 signaling leads to apoptosis of leukemic large granular lymphocytes and decreased Mcl-1 expression. J Clin Invest 2001; 107: 351–362.

11.

Shouda

Hiraoka

Komiya

: Suppression of IL-6 production and proliferation by blocking STAT3 activation in malignant soft tissue tumor cells. Cancer Lett 2006; 231: 176–184.

12.

Heinrich

Behrmann

Haan

: Principles of interleukin (IL)-6-type cytokine signalling and its regulation. Biochem J 2003; 374: 1–20.

13.

Shen

Devgan

Darnell

Jr : Constitutively activated STAT3 protects fibroblasts from serum withdrawal and UV-induced apoptosis and antagonizes the proapoptotic effects of activated STAT1. Proc Natl Acad Sci USA 2001; 98: 1543–1548.

14.

Fuke

Shiraki

Sugimoto

: Jak inhibitor induces S phase cell-cycle arrest and augments TRAIL-induced apoptosis in human hepatocellular carcinoma cells. Biochem Biophys Res Commun 2007; 363: 738–744.

15.

Gritsko

Williams

Turkson

: Persistent activation of stat3 signaling induces survivin gene expression and confers resistance to apoptosis in human breast cancer cells. Clin Cancer Res 2006; 12: 11–19.

16.

Aoki

Feldman

Tosato

: Inhibition of STAT3 signaling induces apoptosis and decreases survivin expression in primary effusion lymphoma. Blood 2003 101: 1535–1542.

17.

Kanda

Seno

Konda

: STAT3 is constitutively activated and supports cell survival in association with survivin expression in gastric cancer cells. Oncogene 2004; 23: 4921–4929.

18.

Konnikova

Kotecki

Kruger

: Knockdown of STAT3 expression by RNAi induces apoptosis in astrocytoma cells. BMC Cancer 2003; 3: 23.

19.

Lin

Lai

Chirieac

: Constitutive activation of JAK3/STAT3 in colon carcinoma tumors and cell lines: Inhibition of JAK3/STAT3 signaling induces apoptosis and cell cycle arrest of colon carcinoma cells. Am J Pathol 2005; 167: 969–980.

20.

Tomita

Kawakami

Uchihara

: Inhibition of constitutively active Jak-STAT pathway suppresses cell growth of human T-cell leukemia virus type 1-infected T-cell lines and primary adult T-cell leukemia cells. Retrovirology 2006; 3: 22.