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Analysis of survival signaling and its application for a new therapeutic strategy of cancers in gastro-intestinal tract and liver.

Research Project

Project/Area Number 14370182
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Gastroenterology
Research InstitutionKumamoto University (2003-2004)
Osaka University (2002)

Principal Investigator

SASAKI Yutaka  Kumamoto University, Graduate School of Medical Sciences, Professor, 大学院・医学薬学研究部, 教授 (70235282)

Co-Investigator(Kenkyū-buntansha) TERASAKI Hisayasu  Kumamoto University, Graduate School of Medical Sciences, Assistant Professor, 大学院・医学薬学研究部, 助手 (50381009)
NAGAHAMA Hiroyasu  Kumamoto University Hospital, Assistant Professor, 医学部附属病院, 助手 (60381000)
田中 基彦  熊本大学, 大学院・医学薬学研究部, 助手 (20346985)
石田 永  大阪大学, 医学部附属病院, 医員(臨床研究)
大川 和良  大阪大学, 医学部附属病院, 医員(臨床研究)
Project Period (FY) 2002 – 2004
Project Status Completed (Fiscal Year 2004)
Budget Amount *help
¥13,200,000 (Direct Cost: ¥13,200,000)
Fiscal Year 2004: ¥2,000,000 (Direct Cost: ¥2,000,000)
Fiscal Year 2003: ¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 2002: ¥7,800,000 (Direct Cost: ¥7,800,000)
KeywordsSurvival signal / apoptosis / liver cancer / p38MAPK / Bcl-2 family / anti-cancer drug / Bcl-2 family / 抗がん剤 / Bcl-2 / 肝細胞癌 / 抗癌剤 / 肝癌
Research Abstract

Different from another form of cell death called necrosis, a morphological-defined cell death, called apoptosis, has been recently observed. Apoptosis is initiated by death ligands, or by a variety of stimuli including chemotherapy, and y-irradiation.
Apoptosis is strictly controlled by a variety of mechanisms at different levels. Inside the cells, the members of Bcl-2 family constitute a first class of regulatory proteins, which act at the mitochondrial level. BAD, a member of Bcl-2 family exerts its pro-apoptotic action on the mitochondrion in the non-phosphorylated state, and forms inactivating dimmers with Bel-XL or Bcl-2 to promote apoptosis. Phosphorylated BAD dissociates from the heterodimeric complex with Bel-XL or Bcl-2,restoring Bel-XL or Bcl-2 function, and activating cell survival signaling. Recent works have indicated that activated BAD kinases including Akt or PKA (A kinase) in the tumor cells play a key role in apoptosis resistance through BAD phosphorylation. We investig … More ated the involvement of intracellular survival signals in human hepatocellular carcinoma(HCC). Both Akt and PKA. were activated in HCCs compared to adjacent non-involved tissues. BAD protein was highly phosphorylated in HCCs compared to uninvolved liver. There was significant correlation between Akt or PKA activity and BAD phosphorylation in HCCs. In addition, inhibitors of these signal transduction cascade induced programmed cell death in human hepatoma cell lines. These observations indicate that survival signal suppresses programmed cell death via BAD phosphorylation in human HCCs, and suggest that it may promote escape from apoptosis to allow HCC tumor progression.
On the other hand, mitogen-activated protein kinase(MAPK) cascade is activated in response to various extracellular stimuli. We examined involvement of p38 MAPK, a MAPK super family, cascade in human HCCs and hepatoma cell lines. In HCCs,MKK6,which is upstream of p38 MAPK, and p38 MAPK activities were significantly lower compared to non-tumorous lesions. There was a significant positive correlation between p38 MAPK and MKK6 activity. Moreover, there was a positive correlation between p38 MAPK and caspase-3 activity. HCCs measuring over 20 mm exhibited lower levels of MKK6 and p38 MAPK activity than did smaller tumors. MKK6 transfection increased p38 MAPK activity, cytochrome c release from the mitochondria to the cytosol, and caspase-3 activity, accompanied by apoptosis in hepatoma cell lines. In contrast, a p38 MAPK specific inhibitor prevents MKK6-induced apoptosis in hepatoma cell lines. These results indicate that the p38 MAPK cascade is consistent with induction of a programmed cell death pathway in hepatoma cells, and suggest that reduction of the p38 MAPK cascade may account, in part, for escape from apoptosis, leading to the progression of human HCC.
Taking together, the modulation of activated survival signals and diminished apoptotic signals may serve as a new therapeutic strategy for cancer therapy. Less

Report

(4 results)
  • 2004 Annual Research Report   Final Research Report Summary
  • 2003 Annual Research Report
  • 2002 Annual Research Report
  • Research Products

    (43 results)

All 2005 2004 2003 2002 Other

All Journal Article (27 results) Book (2 results) Publications (14 results)

  • [Journal Article] New Perspective in Cancer Research and Therapy2005

    • Author(s)
      Sasaki, Y.
    • Journal Title

      Apoptosis resistance in the tumor cells of the liver and gastrointestinal tract(Eds.S.Kuriyama, H.Yoshiji)(Resaerch Signport, Kerala, India)

      Pages: 71-84

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Ninjurin increases p21 expression and induces cellular senescence in human hepatoma cells.2004

    • Author(s)
      Toyama, T., et al.
    • Journal Title

      J.Hepatol. 41

      Pages: 637-643

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Interferon therapy for aged patients with chronic hepatitis C : improved survival in patients exhibiting a biochemical response.2004

    • Author(s)
      Imai, Y., Kasahara, A., Tanaka, H., Okanoue, T., Hiramatsu, N., Tsubouchi, H., Yoshioka, K., Kawata, S., Tanaka, E., Hino, K, Hayashi, K, Tamura, S., Itoh, Y., Sasaki, Y., Kiyosawa, K., Kakumu, S., Okita, K., Hayashi, N.
    • Journal Title

      J.Gastroenterol. 39

      Pages: 1069-1077

    • NAID

      10014116243

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Ninjurin increases p21 expression and induces cellular senescence in human hepatoma cells.2004

    • Author(s)
      Toyama, T., Sasaki, Y., Horimoto, M., Iyoda, K., Yakushijin, T., Ohkawa, K., Takehara, T., Kasahara, A., Araki, T., Hori, M., Hayashi, N.
    • Journal Title

      J.Hepatol 41

      Pages: 637-643

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Ninjurin increases p21 expression and induces cellular senescence in human hepatoma cells.2004

    • Author(s)
      Toyama, T., et al.
    • Journal Title

      J.Hepatol 41

      Pages: 637-643

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Expression and role of MICA and MICB in human hepatocellular carcinomas and their regulation by retinoic acid.2003

    • Author(s)
      Jinushi, M., et al.
    • Journal Title

      Int.J.Cancer 104

      Pages: 354-361

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Annual Research Report 2004 Final Research Report Summary
  • [Journal Article] Involvement of the p38 mitogen-activated protein kinase cascade in human hepatocellular carcinoma.2003

    • Author(s)
      Iyoda, K., et al.
    • Journal Title

      Cancer 97

      Pages: 3017-3026

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Annual Research Report 2004 Final Research Report Summary
  • [Journal Article] Hepatitis C virus core protein differently regulates the JAK-STAT signaling pathway under interleukin-6 and interferon-gamma stimuli.2003

    • Author(s)
      Housui, A., et al.
    • Journal Title

      J.Biol.Chem. 278

      Pages: 28562-28571

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Annual Research Report 2004 Final Research Report Summary
  • [Journal Article] CD1d-mediated stimulation of natural killer T cells selectively activates hepatic natural killer cells to eliminate experimentally disseminated hepatoma cells in murine liver.2003

    • Author(s)
      Miyagi, T., et al.
    • Journal Title

      Int.J.Cancer 106

      Pages: 81-89

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Annual Research Report 2004 Final Research Report Summary
  • [Journal Article] Inhibition of angiotensin II activity enhanced the antitumor effect of cyclooxygenase-2 inhibitors via insulin-like growth factor I receptor pathway.2003

    • Author(s)
      Yasumaru, M., et al.
    • Journal Title

      Cancer Res. 63

      Pages: 6726-6734

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Annual Research Report 2004 Final Research Report Summary
  • [Journal Article] Critical role of MICA/B expression on interferon α-stimutaled dendritic cells in NK cell activation : Impairment in chronic hepatitis C virus infection.2003

    • Author(s)
      Jinushi, M., Takehara, T., Kanto, T., Tatsumi, T., Groh, V., Spies, T., Miyagi, T., Suzuki, T., Sasaki, Y., Hayashi N.
    • Journal Title

      J.Immunol. 170

      Pages: 1249-1256

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Impaired expression of proteasome subunits and human leukocyte antigens class I in human colon cancer cells.2003

    • Author(s)
      Miyagi, T., Tatsumi, T., Takehara, T., Kanto, T., Kuzushita, N., Sugimoto, K., Jinushi, M., Kasahara, A., Sasaki, Y., Hori, M., Hayashi, N.
    • Journal Title

      J.Gastroenterol.Hepatol. 18

      Pages: 32-40

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Changes in gene expression profile -by HCV core protein in cultures liver cells : analysis by DNA array assay.2003

    • Author(s)
      Ohkawa, K., Ishida, H., Nakanishi, F., Housui, A., Sato, A., Ueda, K., Takehara, T., Kasahara, A., Sasaki, Y., Hori, M, Hayashi, N.
    • Journal Title

      Hepatol.Res. 25

      Pages: 396-408

    • NAID

      10016177216

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Intravenous injection of naked plasmid DNA encoding hepatitis B virus (HBV) produces HBV and induces humoral immune response in mice.2003

    • Author(s)
      Suzuki, T., Takehara, T., Ohkawa, K., Ishida, H., Jinushi, M., Miyagi, T., Sasaki, Y., Hayashi, N.
    • Journal Title

      Biochem.Biophys.Res.Commun. 300

      Pages: 784-788

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Expression and role of MICA and MICB in human hepatocellular carcinomas and their regulation by retinoic acid.2003

    • Author(s)
      Jinushi, M., Takehara, T., Tatsumi, T., Kanto, T., Groh, V., Spies, T., Kimura, R., Miyagi, T., Mochizuki, K., Sasaki, Y., Hayashi N.
    • Journal Title

      Int.J.Cancer 104

      Pages: 354-361

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Involvement of the p38 mitogen-activated protein kinase cascade in human hepatocellular carcinoma.2003

    • Author(s)
      Iyoda, K., Sasaki, Y., Horimoto, M., Toyama, T., Yakushijin, T., Sakakibara, M., Takehara, T., Fujimoto, J., Hori, M., Wands, JR., Hayashi, N.
    • Journal Title

      Cancer 97

      Pages: 3017-3026

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Hepatitis C virus core protein differently regulates the JAK-STAT signaling pathway under interleukin-6 and interferon-gamma stimuli.2003

    • Author(s)
      Housui, A., Ohkawa, K., Ishida, H., Sato, A., Nakanishi, F., Ueda, K., Takahara, T., kasahara, A., Sasaki, Y., Hori, M., Hayashi, N.
    • Journal Title

      J.Biol.Chem. 278

      Pages: 28562-28571

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] CD1d-mediated stimulation of natural killer T cells selectively activates hepatic natural killer cells to eliminate experimentally disseminated hepatoma cells in murine liver.2003

    • Author(s)
      Miyagi, T., Takehara, T., Tatsumi, T., Kanto, T, Suzuki, T., Jinushi, M., Sugimoto, K., Sasaki, Y., Hori, M., Hayashi N.
    • Journal Title

      Int.J.Cancer 106

      Pages: 81-89

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Inhibition of angiotensin II activity enhanced the antitumor effect of cyclooxygenase-2 inhibitors via insulin-like growth factor I receptor pathway.2003

    • Author(s)
      Yasumaru, M., Tsuji, S., Tsujii, M., Irie T., Komori, M., Kimura, A., Nishida T., Kakiuchi, Y., Kawai, N., Murata H., Horimoto M., Sasaki, Y., Hayashi, N., Kawano, S., Hori, M.
    • Journal Title

      Cancer Res. 63

      Pages: 6726-6734

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] A novel tool for detecting amyloid deposits in systemic amyloidosis in vitro and in vivo.2003

    • Author(s)
      Ando, Y., Haraoka, K., Terazaki, H., Tanoue, Y., Ishikawa, K., Katsuragi, S., Nakamura, M., Sun, X., Nakagawa, K., Sasamoto, K., Takesako, K., Ishizaki, T., Sasaki, Y., Doh-ura, K.
    • Journal Title

      Lab.Invest. 83

      Pages: 1751-1759

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Tumor necrosis factor-α stimulates invasion of Src acivated intestinal cells.2002

    • Author(s)
      Kawai, N., Tsuji, S., Tsujii, M., Ito, T., Yasumaru, M., Kakiuchi, Y., Kimura, A., Komori, M., Sasaki, Y., Hayashi, N., Kawano, S., Dubos, R., Hori, M.
    • Journal Title

      Gastroenterology 122

      Pages: 331-339

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] A single nucleotide polymorphism of the low molecular mass polypeptide 7 gene influences the interferon response in patients with chronic hepatitis C.2002

    • Author(s)
      Sugimoto, Y., Kuzushita, N., Takehara, T., Kanto, T., Tatsumi, T., Miyagi, T., Jinushi, M., Ohkawa, K., Horimoto, M., Kasahara, A., Hori, M., Sasaki, Y., Hayashi, N.
    • Journal Title

      J.Viral Hepat. 9

      Pages: 377-384

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Cyclooxygenase-2 activity altered the cell-surface carbohydrate antigens on colon cancer cells and enhanced liver metastasis.2002

    • Author(s)
      Kakiuchi, Y., Tsuji, S., Tsujii, M., Kawai, N., Murata H., Yasumaru, M., Kimura, A., Komori, M., Irie T., Miyoshi E., Sasaki, Y., Hayashi, N., Kawano, S., Hori, M.
    • Journal Title

      Cancer Res. 62

      Pages: 1567-1572

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] The enzymatic basis for the conversion of nonfucosylated to fucosylated alpha-fetoprotein by acyclic retinoid treatment in human hepatoma cells : activation of alpha 1-6 fucosyltransferase.2002

    • Author(s)
      Noda, K., Miyoshi, E., Kitada, T., Nakahara, S., Gao, C.X., Honke, K., Shiratori, Y., Moriwaki, H., Sasaki, Y., Hayashi, N., Hori, M., Taniguchi, N.
    • Journal Title

      Tumor Biol. 23

      Pages: 202-211

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] An enzymatic method of analysis for GDP-L-fucose in biological samples, involving high-performance liquid chromatography.2002

    • Author(s)
      Noda, K., Miyoshi, E., Nakahara, S., Ihara, H., Gao, C.X., Honke, K., Yanagitani, S., Sasaki, Y., Hayashi, N., Hori, M., Taniguchi, N.
    • Journal Title

      Anal.Biochem. 310

      Pages: 100-106

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Gastrin enhances gastric mucosal integrity through cyclooxygenase-2 upregulation in rats.2002

    • Author(s)
      Komori, M., Tsuji, S., Sun, W.H., Tsujii, M., Kawai, N., Yasumaru, M., Kakiuchi, Y., Kimura, A., Sasaki, Y., Higashiyama, M., Kawano, S., Hori, M.
    • Journal Title

      Am.J.Physiology : GI and Liver Physiology 283

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Frontiers in Hepatology, HCV/Oxidative Stress and Liver Disease2002

    • Author(s)
      Ohkawa, K., Housui, A., Sasaki, Y., Hayashi, N.
    • Journal Title

      Hepatitis C virus core-mediated alteration of gene expression and signal transduction in the host cell(ed.K.Okita)(Springer-Verlag, Tokyo)

      Pages: 19-31

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Book] "New Perspective in Cancer Research and Therapy" Apoptosis resistance in the tumor cells of the liver and gastrointestinal tract2005

    • Author(s)
      Sasaki, Y.
    • Publisher
      Resaerch Signport, Kerala, India,
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Book] In : "New Perspective in Cancer Research and Therapy" Apoptosis resistance in the tumor cells of the liver and gastrointestinal tract

    • Author(s)
      Sasaki, Y.
    • Publisher
      Resaerch Signport, Kerala, India(In press)
    • Related Report
      2004 Annual Research Report
  • [Publications] Kawai, N., et al.: "Tumor necrosis factor-α stimulates invasion of Src activated intestinal cells"Gastroenterology. 122. 331-339 (2002)

    • Related Report
      2003 Annual Research Report
  • [Publications] Kakiuchi, Y., et al.: "Cyclooxygenase-2 activity altered the cell-surface carbohydrate antigens on colon cancer cells and enhanced liver metastasis"Cancer Res.. 62. 1567-1572 (2002)

    • Related Report
      2003 Annual Research Report
  • [Publications] Jinushi, M., et al.: "Expression and role of MICA and MICB in human hepatocellular carcinomas and their regulation by retinoic acid"Int.J.Cancer. 104. 354-361 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Ivoda.K., et al.: "Involvement of the p38 mitogen-activated protein kinase cascade in human hepatocellular carcinoma"Cancer. 97. 3017-3026 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Housui, A., et al.: "Hepatitis C virus core protein differently regulates the JAK-STAT signaling pathway under interleukin-6 and interferon -gamma stimuli"J.Biol.Chem.. 278. 28562-28571 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Yasumaru, M., et al.: "Inhibition of angiotensin II activity enhanced the antitumor effect of cyclooxygenase-2 inhibitors via insulin-like growth factor I receptor pathway"Cancer Res.. 63. 6726-6734 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] 外山 隆, 佐々木 裕, 林 紀夫: "「Annual Review 消化器 2002」肝臓7.肝細胞癌の病態と診断(分担)"中外医学社. 4 (2002)

    • Related Report
      2003 Annual Research Report
  • [Publications] Kawai, N., et al.: "Tumor necrosis factor-α stimulates invasion of Src acivated intestinal cells"Gastroenterology. 122. 331-339 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Kakiuchi, Y., et al.: "Cyclooxygenase-2 activity altered the cell-surface carbohydrate antigens on colon cancer cells and enhanced liver metastasis"Cancer Res.. 62. 1567-1572 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Jinushi, M., et al.: "Critical role of MICA/B expression on interferon α-stimutaled dendritic cells in NK Cell activation : Impairment in chronic hepatitis C virus infection"J. Immunol. 170. 1249-1256 (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Jinushi, M., et al.: "Expression and role of MICA and MICB in human hepatocellular carcinomas and their regulation by retinoic acid"Int. J. Cancer. 104. 354-361 (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Miyagi, T., et al.: "CD1d-mediated stimulation of natural killer T cells selectively activates hepatic natural killer cells to eliminate experimentally disseminated hepatoma cells in murine liver"Int. J. Cancer. (in press).

    • Related Report
      2002 Annual Research Report
  • [Publications] Iyoda, K., et al.: "Involvement of the p38 mitogen-activated protein kinase cascade in human hepatocellular carcinoma"Cancer. (in press).

    • Related Report
      2002 Annual Research Report
  • [Publications] 外山 隆, 佐々木 裕, 林 紀夫: "「Annual Review 消化器 2002」肝臓7.肝細胞癌の病態と珍断(分担)"中外医学社. 4 (2002)

    • Related Report
      2002 Annual Research Report

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Published: 2002-04-01   Modified: 2016-04-21  

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