Defective Jak-Stat activation in renal cell carcinoma is associated with interferon-alpha resistance.
Chemotherapy is ineffective against metastatic renal cell carcinoma (RCC). Interferon (IFN)-alpha has become the most common agent used in clinical therapy to overcome this malignant tumor, although a satisfactory response has not been achieved and the mechanism of resistance of RCC to IFN-alpha remains unclear. The purpose of the present study was to evaluate the susceptibility of RCC cells to IFN-alpha and clarify the mechanism of IFN-alpha resistance in RCC. Six RCC cell lines and three types of IFN-alpha were used, and the expression, activation and effects of transfection of possible proteins or factors reported to be involved in IFN-alpha signaling were examined to clarify the mechanism of resistance. The results suggest that the resistance of RCC to IFN-alpha is associated with the lack of Jak1, Tyk2 and Stat1 expression and defective Jak-Stat activation, but not with a lack of IFN-alpha receptor, suppressors of cytokine signaling induction or other factors examined. Moreover, phosphorylation of Jak-Stat pathway components and reversion of IFN-alpha resistance in RCC were observed upon transfection with Jak1, Tyk2 or Stat1 vector. These results suggest that restoring the expression of Jak or Stat1 might strikingly increase the susceptibility of RCC to IFN-alpha and may be a new strategy for improving the response of RCC to IFN-alpha treatment. The Jak-Stat pathway should therefore be an appropriate target for the treatment of RCC.
Shang
Donghao
D
Department of Urology, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan.
Liu
Yuting
Y
Ito
Noriyuki
N
Kamoto
Toshiyuki
T
Ogawa
Osamu
O
D002292:Carcinoma, Renal Cell / Q000188:drug therapy*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D004789:Enzyme Activation; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology*; D053613:Janus Kinase 1 / Q000378:metabolism*; D007680:Kidney Neoplasms / Q000188:drug therapy*; D010766:Phosphorylation; D053633:Receptor, Interferon alpha-beta / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D053634:TYK2 Kinase / Q000378:metabolism; D014162:Transfection
D016898:Interferon-alpha; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D053633:Receptor, Interferon alpha-beta; D053613:Janus Kinase 1; D053634:TYK2 Kinase