Elucidation of pathophysiological significance of LIF and development of new treatment strategy in prostate cancer

• Project/Area Number: 14571522
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Urology
• Research Institution: Keio University
• Principal Investigator: NAKASHIMA Jun Keio University, Department of Medicine, Assistant Professor, 医学部, 講師 (10167546)
• Co-Investigator(Kenkyū-buntansha): HORIGUCHI Yutaka Keio University, Department of Medicine, Assistant Professor, 医学部, 講師 (60229234) ; OYA Mototsugu Keio University, Department of Medicine, Assistant Professor, 医学部, 講師 (00213885) ; OHIGASHI Takashi Keio University, Department of Medicine, Assistant Professor, 医学部, 講師 (80185371) ; MURAI Masaru Keio University, Department of Medicine, Professor, 医学部, 教授 (90101956)
• Project Period (FY): 2002 – 2004
• Project Status: Completed (Fiscal Year 2004)
• Budget Amount: ¥3,300,000 (Direct Cost: ¥3,300,000); Fiscal Year 2004: ¥700,000 (Direct Cost: ¥700,000); Fiscal Year 2003: ¥1,200,000 (Direct Cost: ¥1,200,000); Fiscal Year 2002: ¥1,400,000 (Direct Cost: ¥1,400,000)
• Keywords: prostate cancer / LIF / IL-6 / cell growth / cachexia / ヌードマウス

Research Abstract

In vitro culture of JCA-1 cells produced a time dependent increase in medium levels of leukemia inhibitory factor (LIF). An NFkappaB inhibitor produced an inhibitory effect on LIF production in JCA cells. On the other hand, recombinant LIF demonstrated no significant effects on cell growth in prostate cancer cell lines, PC3, DU145 and JCA-1 cells. Serum levels of LIF in nude mice having JCA-1 tumors and PC3 tumors were increased, respectively, whereas those in control nude mice without tumors were not detected. At the same time, JCA-1 tumor-bearing mice produced a decrease in body weight 28 days after inoculation, although mice without tumors showed an increase in body weight. In vitro culture of JCA-1 cells also produces IL-6. Serum levels of IL-6 were also significantly elevated in JCA-1 tumor bearing nude mice accompanied with a loss of body weight when compared with control mice without tumors. Then, serum levels of LIF and IL-6 were measured in patients with prostate cancer. Serum levels of LIF were not detected in a majority of untreated patients and patients with progression after endocrine therapy. On the other hand, serum IL-6 levels were significantly elevated in untreated patients with stage D disease when compared with stage A, B and C patients. Serum IL-6 levels further increased in patients with progression after endocrine therapy. The serum total protein and albumin levels, hemoglobin levels, and body mass index of the patients with higher serum IL-6 levels were significantly lower than the corresponding values in patients with lower serum IL-6 levels. Significant correlation between serum IL-6 and serum albumin levels, hemoglobin levels, body mass index and performance status was found. An NFkappaB inhibitor produced statistically significant increase in body weight, epididymal fat and gastrocnemius muscle weight in JCA-1 tumor bearing nude mice, when compared to control mice. Hematocrit, serum albumin and triglyceride levels were significantly higher and serum IL-6 levels were significantly lower in treated mice than control mice. These results suggest that serum IL-6 may be associated with cachexia and an NFkappaB inhibitor may prevent the development of cancer cachexia induced by prostate cancer through the suppression of IL-6 in an animal model.

Research Products

• [Journal Article] Inhibition of Wnt signaling downregulates Akt activity and induces chemosensitivity in PTEN-mutated prostate cancer cells. (2005)
  • Author(s): Ohigashi T, Mizuno R, Nakashima J, et al.
  • Journal Title: Prostate 62(1) Pages: 61-68
• [Journal Article] Differential expression of activator protein-2 isoforms in renal cell carcinoma. (2004)
  • Author(s): Oya, M., Mikami, S., Mizuno, R., Miyajima, A., Horiguchi, Y., Nakashima, J., Marumo, K., Mukai, M., Murai, M.
  • Journal Title: Urology 64 Pages: 162-167
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Inhibition of MKP-1 expression potentiates JNK related apoptosis in renal cancer cells. (2004)
  • Author(s): Mizuno, R., Oya, M., Shiomi, T., Marumo, K., Okada, Y., Murai, M.
  • Journal Title: Journal of Urology 172 Pages: 723-727
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Inhibition of the ubiquitin-proteasome pathway activates stress kinases and induces apoptosis in renal cancer cells. (2004)
  • Author(s): Ishizawa, J., Yoshida S., Oya, M., Mizuno, R., Shinojima, T., Marumo, K., Murai, M.
  • Journal Title: International Journal of Oncology 25 Pages: 697-702
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Suppression of hormone-refractory prostate cancer by a novel nuclear factor κB inhibitor in nude mice (2003)
  • Author(s): KIKUCHI E., HORIGUCHI Y., NAKASHIMA J, KURODA K., OYA M., OHIGASHI T., TAMAHASHI N., SHIMA Y., UMEZAWA K., MURAI M
  • Journal Title: Cancer research 63 Pages: 107-110
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Enhancement of diethylstilbestrol induced cytotoxicity by bcl-2 antisense oligodeoxynucleotides and a glutathione depletor for prostate cancer (2003)
  • Author(s): KIKUCHI E., NAKASHIMA J., HORIGUCHI Y., OYA M., OHIGASHI T., MURAI M
  • Journal Title: The Journal of Urology 169 Pages: 730-734
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Pediction of extraprostatic cancer by prostate specific antigen density, endorectal MRI, and biopsy Gleason score in clinically localized prostate cancer (2003)
  • Author(s): HORIGUCHI A., NAKASHIMA J., HORIGUCHI Y., NAKAGAWA K., OYA M., OHIGASHI T., MARUMO K., MURAI M.
  • Journal Title: Prostate 56 Pages: 23-29
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Increased nuclear factor-κB activation is related to the tumor development of renal cell carcinoma. (2003)
  • Author(s): Oya, M., Takayanagi, A., Horiguchi, A., Mizuno, R., Ohtsubo, M., Marumo, K., Shimizu, N., Murai, M.
  • Journal Title: Carcinogenesis 24 Pages: 377-384
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Increased activation of CCAAT/enhancer binding protein-β correlates with the invasiveness of renal cell carcinoma. (2003)
  • Author(s): Oya, M., Horiguchi, A., Mizuno, M., Marumo, K., Murai, M.
  • Journal Title: Clinical Cancer Research 9 Pages: 1021-1027
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Elevated AKT activation and its impact on clinicopathological features of renal cell carcinoma. (2003)
  • Author(s): Horiguchi, A., Oya, M., Shimada, T., Uchida, A., Marumo, K., Murai, M
  • Journal Title: Journal of Urology 169 Pages: 710-713
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Eiji Kikuchi, Jun Nakashima et al.: "Enhancement of diethylstilbestrol induced cytotoxicity by bcl-2antisense oligodeoxynucleotides and a glutathione depletor for prostate cancer"J Urol. 169. 730-734 (2003)