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Restoration of immune susceptibility to cancer cells regulated by autophagy and hypoxic responses

Research Project

Project/Area Number 25430150
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Tumor therapeutics
Research InstitutionShimane University

Principal Investigator

HARASHIMA Nanae  島根大学, 医学部, 助教 (60345311)

Project Period (FY) 2013-04-01 – 2016-03-31
Project Status Completed (Fiscal Year 2015)
Budget Amount *help
¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000)
Fiscal Year 2015: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2014: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2013: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
Keywords低酸素 / 癌 / 免疫 / 治療抵抗性 / オートファジー / アポトーシス
Outline of Final Research Achievements

In the human pancreatic cancer cells which showed resistance to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), as an anticancer drug, I investigated to restore the sensitivity to TRAIL and elucidate its cellular mechanisms. Pifithrin-mu, an inhibitor of autophagy or ABT-263, a Bcl-2 family inhibitor which targets Bcl-2, Bcl-xL, and Bcl-w significantly enhanced the sensitivity to TRAIL in human pancreatic cancer cells. Knockdown of HIF-2alpha, but not HIF-1alpha, using siRNA increased the susceptibility of pancreatic cancer cells to TRAIL via decreased the expression of anti-apoptotic protein survivin, and induced antitumor effects. These results suggest that inhibition of HIF-2alpha, autophagy, or anti-apoptotic molecules can enhance the efficacy of immune therapies to cancers.

Report

(4 results)
  • 2015 Annual Research Report   Final Research Report ( PDF )
  • 2014 Research-status Report
  • 2013 Research-status Report
  • Research Products

    (38 results)

All 2016 2015 2014 2013

All Journal Article (11 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 11 results,  Open Access: 8 results,  Acknowledgement Compliant: 5 results) Presentation (27 results) (of which Int'l Joint Research: 2 results)

  • [Journal Article] Detection of an immunogenic HERV-E envelope with selective expression in clear cell kidney cancer2016

    • Author(s)
      Cherkasova E., Scrivani C., Doh S., Weisman Q., Takahashi Y., Harashima N., Yokoyama H., Srinivasan R., Linehan WM., Lerman MI., and Childs RW.
    • Journal Title

      Cancer Research

      Volume: 76 (8) Issue: 8 Pages: 2177-2185

    • DOI

      10.1158/0008-5472.can-15-3139

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] The roles of ROS and caspases in TRAIL-Induced apoptosis and necroptosis in human pancreatic cancer cells2015

    • Author(s)
      Zhang M, Harashima N, Moritani T, Huang W, Harada M.
    • Journal Title

      PLoS One

      Volume: 10 (5) Issue: 5 Pages: e0127386-e0127386

    • DOI

      10.1371/journal.pone.0127386

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Identification of programmed death ligand 1-derived peptides capable of inducing cancer-reactive cytotoxic T lymphocytes from HLA-A24+ patients with renal cell carcinoma2015

    • Author(s)
      Minami T., Minami T., Shimizu N., Yamamoto Y., De Velasco MA., Nozawa M., Yoshimura K., Harashima N., Harada M., Uemura H.
    • Journal Title

      Journal of Immunotherapy

      Volume: 38 (7) Issue: 7 Pages: 285-291

    • DOI

      10.1097/cji.0000000000000090

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Bcl-xL inhibition by molecular-targeting drugs sensitizes human pancreatic cancer cells2015

    • Author(s)
      Hari Y., Harashima N., Tajima Y., Harada M.
    • Journal Title

      Oncotarget

      Volume: 6 (39) Issue: 39 Pages: 41902-41915

    • DOI

      10.18632/oncotarget.5881

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Intermittent chemotherapy can retain the therapeutic potential of anti-CD137 antibody during the late tumor-bearing state.2015

    • Author(s)
      Tongu M, Harashima N, Tamada K, Chen L, Harada M
    • Journal Title

      Cancer Science

      Volume: 106 Issue: 1 Pages: 9-17

    • DOI

      10.1111/cas.12568

    • NAID

      120005982740

    • Related Report
      2014 Research-status Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] New polycomb group protein enhancer of zeste homolog (EZH) 2-derived peptide with the potential to induce cancer-reactive cytotoxic T lymphocytes in prostate cancer patients with HLA-A3 supertype alleles2015

    • Author(s)
      Minami T, Minami T, Shimizu N, Yamamoto Y, De Velasco M A, Nozawa M, Yoshimura K, Harashima N, Harada M, Uemura H.
    • Journal Title

      International Immunopharmacology

      Volume: 26 Issue: 1 Pages: 133-138

    • DOI

      10.1016/j.intimp.2015.03.023

    • Related Report
      2014 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Transfection of poly(I:C) can induce ROS-triggered apoptosis and IFN--mediated growth arrest in human renal cell carcinoma cells via innate adjuvant receptors and the 2-5A system2014

    • Author(s)
      Harashima N, Minami T, Uemura H, Harada M
    • Journal Title

      Molecular Cancer

      Volume: 13 Issue: 1 Pages: 217-217

    • DOI

      10.1186/1476-4598-13-217

    • Related Report
      2014 Research-status Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Bcl-2 family inhibition sensitizes human prostate cancer cells to docetaxel and promotes unexpected apoptosis under caspase-9 inhibition2014

    • Author(s)
      Tamaki H, Harashima N, Hiraki M, Aichi N, Nishimura N, Shiina H, Naora K, Harada M.
    • Journal Title

      Oncotarget

      Volume: 5 (22) Pages: 11399-11412

    • Related Report
      2014 Research-status Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Identification of erythropoietin receptor-derived peptides having the potential to induce cancer-reactive cytotoxic T lymphocytes from HLA-A24+ patients with renal cell carcinoma.2014

    • Author(s)
      Minami T, Minami T, Shimizu N, Yamamoto Y, De Velasco M, Nozawa M, Yoshimura K, Harashima N, Harada M, Uemura H.
    • Journal Title

      International Immunopharmacology

      Volume: 20 Issue: 1 Pages: 59-65

    • DOI

      10.1016/j.intimp.2014.02.018

    • Related Report
      2013 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] The HSP70 and autophagy inhibitor pifithrin-mu enhances the antitumor effects of TRAIL on human pancreatic cancer2013

    • Author(s)
      Monma H, Harashima N, et al.
    • Journal Title

      Mol Cancer Ther

      Volume: 12 Issue: 4 Pages: 341-351

    • DOI

      10.1158/1535-7163.mct-12-0954

    • Related Report
      2013 Research-status Report
    • Peer Reviewed
  • [Journal Article] Pifithrin-mu, an inhibitor of heat-shock protein 70, can increase the antitumor effects of hyperthermia against human prostate cancer cells2013

    • Author(s)
      Sekihara M, Harashima N, Tongu M, Tamaki Y, Uchida N, Inomata T, Harada M.
    • Journal Title

      PLoS One

      Volume: 8 Issue: 11 Pages: e78772-e78772

    • DOI

      10.1371/journal.pone.0078772

    • Related Report
      2013 Research-status Report
    • Peer Reviewed
  • [Presentation] HIF-2alpha, but not HIF-1alpha, determines immune resistance of pancreatic cancer cells to TRAIL and T cells via survivin2015

    • Author(s)
      Harada M., Harashima N.
    • Organizer
      第44回日本免疫学会
    • Place of Presentation
      札幌コンベンションセンター(北海道)
    • Year and Date
      2015-11-18
    • Related Report
      2015 Annual Research Report
  • [Presentation] Bcl-xL inhibition sensitizes human pancreatic cancer cells to TRAIL2015

    • Author(s)
      波里瑶子、原嶋奈々江、田島義証、原田守
    • Organizer
      第74回日本癌学会総会
    • Place of Presentation
      名古屋国際会議場(愛知)
    • Year and Date
      2015-10-08
    • Related Report
      2015 Annual Research Report
  • [Presentation] HIF-2alpha regulates susceptibility of human pancreatic cancer cells to TRAIL- and T cell-mediated cytotoxicity via survivin2015

    • Author(s)
      原嶋奈々江、秋元美穂、竹永啓三、原田守
    • Organizer
      第74回日本癌学会総会
    • Place of Presentation
      名古屋国際会議場(愛知)
    • Year and Date
      2015-10-08
    • Related Report
      2015 Annual Research Report
  • [Presentation] Regulatory roles of HIF-2alpha and survivin in TRAIL- and gannma-deltaT cell-mediated cytotoxicity of human pancreatic cancer cells2015

    • Author(s)
      Harashima N., Harada M.
    • Organizer
      19th JACI & 23rd MMCB, がん免疫療法・マクロファージ国際会議2015
    • Place of Presentation
      東京大学(東京)
    • Year and Date
      2015-07-09
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research
  • [Presentation] The role of ROS and caspases in TRAIL-induced apoptosis and necroptosis in human pancreatic cancer cells2015

    • Author(s)
      Harada M., Harashima N.
    • Organizer
      19th JACI & 23rd MMCB, がん免疫療法・マクロファージ国際会議2015
    • Place of Presentation
      東京大学(東京)
    • Year and Date
      2015-07-09
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Combination of low-dose and intermittent chemotherapy with cyclophosphamide and gemcitabine restores efficacy of anti-CD137 antibody therapy at the late tumor-bearing state2014

    • Author(s)
      Harada M, Tamada K, Harashima N
    • Organizer
      第43回日本免疫学会
    • Place of Presentation
      国立京都国際会館(京都市)
    • Year and Date
      2014-12-10 – 2014-12-12
    • Related Report
      2014 Research-status Report
  • [Presentation] HIF-2alphaの阻害はヒト膵がん細胞のTRAIL感受性を増強する2014

    • Author(s)
      原嶋奈々江、秋元美穂、竹永啓三、原田守
    • Organizer
      第12回がんとハイポキシア研究会
    • Place of Presentation
      ホテルマリターレ創世佐賀(佐賀市)
    • Year and Date
      2014-11-21 – 2014-11-22
    • Related Report
      2014 Research-status Report
  • [Presentation] Bcl-2 family inhibitors effectively sensitize human pancreatic cancer cells to TRAIL2014

    • Author(s)
      Hari Y, Harashima N, Kidani A, Hayashi H, Kawabata Y, Harada M, Yano S, Tajima Y
    • Organizer
      45th Anniversary Meeting of APA (American pancreatic association) /JPS(日本膵臓学会)
    • Place of Presentation
      Hapuna Beach Prince Hotel, Big Island, Hawaii, U.S.A.
    • Year and Date
      2014-11-05 – 2014-11-08
    • Related Report
      2014 Research-status Report
  • [Presentation] Autophagy inhibitors enhance TRAIL-Induced antitumor effects on human pancreatic cancer cells2014

    • Author(s)
      Monma H, Harashima N, Hari Y, Kishi S, Tajima Y, Harada M
    • Organizer
      45th Anniversary Meeting of APA (American pancreatic association) /JPS(日本膵臓学会)
    • Place of Presentation
      Hapuna Beach Prince Hotel, Big Island, Hawaii, U.S.A.
    • Year and Date
      2014-11-05 – 2014-11-08
    • Related Report
      2014 Research-status Report
  • [Presentation] ABT-263 sensitizes PC3 prostate cancer cells to docetaxel2014

    • Author(s)
      玉木宏樹、原嶋奈々江、原田守
    • Organizer
      第73回日本癌学会
    • Place of Presentation
      パシフィコ横浜(横浜市、神奈川)
    • Year and Date
      2014-09-25 – 2014-09-27
    • Related Report
      2014 Research-status Report
  • [Presentation] Bcl-2 family inhibitor ABT-263 unveils the resistance to TRAIL-induced apoptosis in human pancreatic cancer cells2014

    • Author(s)
      波里瑶子、原嶋奈々江、門馬浩行、田島義証、原田守
    • Organizer
      第73回日本癌学会
    • Place of Presentation
      パシフィコ横浜(横浜市、神奈川)
    • Year and Date
      2014-09-25 – 2014-09-27
    • Related Report
      2014 Research-status Report
  • [Presentation] Inhibition of HIF-2alpha sensitizes human pancreatic cancer cells to TRAIL2014

    • Author(s)
      原嶋奈々江、波里瑶子、門馬浩行、秋元美穂、竹永啓三、田島義証、原田守
    • Organizer
      第73回日本癌学会
    • Place of Presentation
      パシフィコ横浜(横浜市、神奈川)
    • Year and Date
      2014-09-25 – 2014-09-27
    • Related Report
      2014 Research-status Report
  • [Presentation] Bcl-2 family阻害剤併用によるヒト膵癌細胞のTRAIL抵抗性の克服2014

    • Author(s)
      波里瑶子、原嶋奈々江、門馬浩行、田島義証、原田守
    • Organizer
      第18回日本がん免疫学会
    • Place of Presentation
      ひめぎんホール(松山市、愛媛)
    • Year and Date
      2014-07-30 – 2014-08-01
    • Related Report
      2014 Research-status Report
  • [Presentation] 低酸素誘導因子hypoxia-inducible factor阻害によるヒト膵癌細胞のTRAIL抵抗性の増強2014

    • Author(s)
      原嶋奈々江、波里瑶子、門馬浩行、秋元美穂、竹永啓三、原田守
    • Organizer
      第18回日本がん免疫学会
    • Place of Presentation
      ひめぎんホール(松山市、愛媛)
    • Year and Date
      2014-07-30 – 2014-08-01
    • Related Report
      2014 Research-status Report
  • [Presentation] ヒト膵癌細胞に対するTRAILとchloroquineの併用効果の検討2014

    • Author(s)
      門馬浩行、原嶋奈々江、波里瑶子、田島義証、原田守
    • Organizer
      第18回日本がん免疫学会
    • Place of Presentation
      ひめぎんホール(松山市、愛媛)
    • Year and Date
      2014-07-30 – 2014-08-01
    • Related Report
      2014 Research-status Report
  • [Presentation] Autophagy阻害剤を用いたヒト膵癌に対するTRAILの抗腫瘍効果増強の検討2014

    • Author(s)
      門馬浩行, 原田守, 波里瑶子, 原嶋奈々江, 高井清江, 木谷昭彦, 林彦多, 川畑康成, 矢野誠司, 田島義証
    • Organizer
      第69回 日本消化器外科学会総会
    • Place of Presentation
      ホテルハマツ/郡山市民文化センター(郡山市、福島)
    • Year and Date
      2014-07-16 – 2014-07-18
    • Related Report
      2014 Research-status Report
  • [Presentation] Bcl-2ファミリー阻害剤併用によるヒト前立腺癌細胞のDocetaxel感受性の増強2014

    • Author(s)
      玉木宏樹、西村信弘、原嶋奈々江、原田守、直良浩司
    • Organizer
      日本薬学会第134年会
    • Place of Presentation
      ホテル日航熊本、鶴屋ホール、熊本大学他(熊本)
    • Related Report
      2013 Research-status Report
  • [Presentation] 膵癌細胞に対するTRAILと新規HSP70阻害剤pifithrin-muの併用効果と作用機序2013

    • Author(s)
      門馬浩行, 原嶋奈々江, 木谷昭彦, 西健, 川畑 康成, 矢野誠司, 田島 義証
    • Organizer
      第44回日本膵臓学会
    • Place of Presentation
      仙台国際センター(仙台)
    • Related Report
      2013 Research-status Report
  • [Presentation] 低用量chemotherapyと抗CD137抗体の併用により誘導される持続的な抗腫瘍免疫応答2013

    • Author(s)
      頓宮美樹、原嶋奈々江、山田高也、岡野慎士、玉田耕治、原田守
    • Organizer
      第17回日本がん免疫学会
    • Place of Presentation
      ANAクラウンプラザホテル宇部(山口)
    • Related Report
      2013 Research-status Report
  • [Presentation] HSP70阻害剤pifithrin-muがPanc-1膵癌細胞に対するTRAIL誘導性アポトーシスを増強する2013

    • Author(s)
      門馬浩行、原嶋奈々江、波里瑶子、田島義証、原田守
    • Organizer
      第17回日本がん免疫学会
    • Place of Presentation
      ANAクラウンプラザホテル宇部(山口)
    • Related Report
      2013 Research-status Report
  • [Presentation] Poly(I:C)トランスフェクションによるROS産生を伴った癌細胞死誘導とその活性化経路2013

    • Author(s)
      原嶋奈々江、岡野慎士、原田守
    • Organizer
      第17回日本がん免疫学会
    • Place of Presentation
      ANAクラウンプラザホテル宇部(山口)
    • Related Report
      2013 Research-status Report
  • [Presentation] Persistent antitumor immunity after the combination therapy with low-dose chemotherapy and anti-CD137 (4-1BB) antibody2013

    • Author(s)
      頓宮美樹、原嶋奈々江、山田高也、岡野慎士、玉田耕治、原田守
    • Organizer
      第72回日本癌学会
    • Place of Presentation
      パシフィコ横浜(横浜)
    • Related Report
      2013 Research-status Report
  • [Presentation] Restoration of the TRAIL susceptibility of human pancreatic cancer cells by inhibition of Bcl-xL2013

    • Author(s)
      原嶋奈々江、波里瑶子、門馬浩行、田島義証、原田守
    • Organizer
      第72回日本癌学会
    • Place of Presentation
      パシフィコ横浜(横浜)
    • Related Report
      2013 Research-status Report
  • [Presentation] Mechanisms of an HSP-70 inhibitor pifithrin-mu to enhance TRAIL-induced apoptosis of pancreatic cancer cells2013

    • Author(s)
      門馬浩行、原嶋奈々江、波里瑶子、田島義証、原田守
    • Organizer
      第72回日本癌学会
    • Place of Presentation
      パシフィコ横浜(横浜)
    • Related Report
      2013 Research-status Report
  • [Presentation] A novel HSP-70 inhibitor pifithrin-mu enhances the antitumor effect of radiation on human prostate cancer2013

    • Author(s)
      関原和正、原嶋奈々江、内田伸恵、猪俣泰典、原田守
    • Organizer
      第72回日本癌学会
    • Place of Presentation
      パシフィコ横浜(横浜)
    • Related Report
      2013 Research-status Report
  • [Presentation] Poly(I:C), an innate adjuvant receptor ligand, can induce the antitumor effects on human breast cancer cells2013

    • Author(s)
      Touko Inao, Nanae Harashima, Yutaka Yamamoto, Mamoru Harada, Hirotaka Iwase
    • Organizer
      36th Annual SABCS
    • Place of Presentation
      San Antonio (U.S.A)
    • Related Report
      2013 Research-status Report
  • [Presentation] Long-lasting suppression of CT26 growth after low-dose chemotherapy with cyclophosphamide plus gemcitabine, followed by anti-CD137 antibody2013

    • Author(s)
      原田守、岡野慎士、玉田耕治、原嶋奈々江
    • Organizer
      第42回日本免疫学会
    • Place of Presentation
      幕張メッセ(千葉県幕張市)
    • Related Report
      2013 Research-status Report

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Published: 2014-07-25   Modified: 2019-07-29  

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