YB-1 suppression induces STAT3 proteolysis and sensitizes renal cancer to interferon-α.
Renal cell carcinoma (RCC) accounts for 80-95 % of kidney tumors, and approximately 30 % of RCC patients have metastatic disease at diagnosis. Conventional chemotherapy is not effective in patients with metastatic RCC (MRCC); therefore, immunotherapy with interferon-α (IFN-α) has been employed to improve survival. However, the response rate of MRCC to IFN-α therapy is low. We previously reported that a signal transducer and activator 3 (STAT3) polymorphism was a useful diagnostic marker to predict the response to IFN-α therapy in patients with MRCC. Therefore, we hypothesized the inhibition of STAT3 in the addition of IFN-α therapy might be useful. Moreover, the blockage of STAT3 itself has been reported to enhance the antitumor effects. However, because IFN-α is thought to elicit its therapeutic effect via enhancement of an antitumor immune response mediated by lymphocytes that can be activated by IFN-α administrations, it is probable that the suppression of STAT3 in vivo relates to autoimmune disorders. In the present study, we found Y-box binding protein-1 (YB-1) was poorly expressed in T lymphocytes, as compared with cancer tissues. YB-1 was reported to have an important effect on the STAT3 pathway. Suppression of STAT3 by YB-1 inhibition did not seem to enhance the potential risk for autoimmune disorders. Moreover, we found sensitivity to IFN-α was increased by YB-1 suppression, and this suppression did not down-regulate IFN-α activation of T lymphocytes.
Department of Urology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan. atakeuchi@prostatecentre.com
Ario
A
Takeuchi
Masaki
M
Shiota
Katsunori
K
Tatsugami
Akira
A
Yokomizo
Kentaro
K
Kuroiwa
Takashi
T
Dejima
Shingo
S
Tanaka
Momoe
M
Itsumi
Masatoshi
M
Eto
Seiji
S
Naito
D000818:Animals; D002292:Carcinoma, Renal Cell / Q000378:metabolism* / Q000473:pathology / Q000628:therapy*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology / Q000627:therapeutic use*; D007680:Kidney Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D059748:Proteolysis; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D051840:Y-Box-Binding Protein 1 / Q000037:antagonists & inhibitors* / Q000494:pharmacology
D016898:Interferon-alpha; D050796:STAT3 Transcription Factor; D051840:Y-Box-Binding Protein 1; C070856:YBX1 protein, human