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Cyclin A confers CDDP resistance to endometrial carcinoma cells via activation of PI-3K pathway

Research Project

Project/Area Number 17591726
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Obstetrics and gynecology
Research InstitutionSHINSHU UNIVERSITY

Principal Investigator

KATO Kiyoshi  Shinshu University, School of Medicine, assistant professor, 医学部附属病院, 助手 (40334908)

Co-Investigator(Kenkyū-buntansha) SHIOZAWA Tanri  Shinshu University, School of Medicine, associate professor, 医学部, 助教授 (20235493)
KONISHI Ikuo  Shinshu University, School of Medicine, professor, 医学部, 教授 (90192062)
Project Period (FY) 2005 – 2006
Project Status Completed (Fiscal Year 2006)
Budget Amount *help
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2006: ¥1,700,000 (Direct Cost: ¥1,700,000)
Fiscal Year 2005: ¥1,800,000 (Direct Cost: ¥1,800,000)
Keywordscyclin A / apoptosis / chemoresistanse / Endometrial carcinoma / periplakin / chemotherapy / PI3-kinase pathway / MAP kinase
Research Abstract

Our objective of this study was to examine the hypothesis that the cyclinA overexpression in endometrial cancer may influence the growth of the endometrial caricnima cell as well as the sensitivity to anticancer drugs.
To access this hypothesis, we first established a stable cyclin A expressing endometrial carcinoma cell line (cyc A HHUA), which demonstrated an increased proliferative activity and resistance to chemotherapeutic agents. We also observed that the increased resistance was accompanied with reduced apoptosis after the exposure to anticancer drugs. The following immunoblotting study revealed that the resistance was in part due to the increased expressions of antiapoptotic factor, Bcl-2 as well as the inactivation of proapoptotic factor, Bad. We then evaluated the involvement of PI3K-Akt antiapoptotic pathway. Activating phosphorylation was augmented after the exposure to CDDP in cyc A HHUA compared with the control, suggesting that the PI-3K pathway plays an important role in cyclinA-induced CDDP resistance.
To further examine the mechanisms of cyclin A-induced CDCP resistance, we performed an oligonucleotide array analysis between the cycA HHUA and control HHUA to identify new molecules involved in the antiapoptotic effects of cyclinA. The analysis revealed that an Akt-binding protein, periplakin (PPL), was up-regulated in cyc A HHUA. Immunoprecipitation showed that the Akt-binding fraction of PPL was also increased along with the increased expression of cyclin A. Transfection of PPL-specific siRNA successfully reduced Akt phosphorylation, indicating that the binding of PPL to Akt stabilized the PI3K-Akt pathway signaling.
In conclusion, we have newly revealed that the cyclin A exerted an antiapoptotic effect repoponsible for CDDP resistance in endometrial cancer cells, and that the effect was mediated via the stabilization of Akt pathway by PPL.

Report

(3 results)
  • 2006 Annual Research Report   Final Research Report Summary
  • 2005 Annual Research Report
  • Research Products

    (22 results)

All 2007 2006 2005

All Journal Article (22 results)

  • [Journal Article] Hedgehog signal pathway is activated in ovarian carcinomas, correlating with cell proliferation : It's inhibition leads to growth suppression and apoptosis.2007

    • Author(s)
      Chen X, Horiuchi A, Kikuchi N, Osada R, Yoshida J, Shiozawa T, Konishi I
    • Journal Title

      Cancer Sci 98

      Pages: 68-76

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Annual Research Report 2006 Final Research Report Summary
  • [Journal Article] Overexpression of hedgehog signaling molecules and its involvement in the proliferation of endometrial carcinoma cells.2007

    • Author(s)
      Feng YZ, Shiozawa T, Miyamoto T, Kashima H, Kurai M, Suzuki A, Ying-Song J, Konishi I
    • Journal Title

      Clin Cancer Res 13(5)

      Pages: 1389-1398

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Annual Research Report 2006 Final Research Report Summary
  • [Journal Article] Overexpression of hedgehog-signaling molecules and its involvement in the proliferation of endometrial carcinoma cells.2007

    • Author(s)
      Feng YZ, Shiozawa T, Miyamoto T, Kashima H, Kurai M, Suzuki A, Ying-Song J, Konishi I
    • Journal Title

      Clin Cancer Res 13

      Pages: 1389-1398

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Hedgehog signal pathway is activated in ovarian carcinomas correlating with the cell proliferation : Its inhibition leads to the growth suppression and apoptosis.2007

    • Author(s)
      Chen X, Horiuchi A, Kikuchi N, Osada R, Yoshida J, Shiozawa T, Konishi I
    • Journal Title

      Cancer Sci 98

      Pages: 68-76

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Early endometrial carcinoma : clinicopathology, hormonal aspects,molecular genetics,diagnosis,and treatment.(Review)2006

    • Author(s)
      Shiozawa T, Ikuo K
    • Journal Title

      Int J Clin Oncol 11(1)

      Pages: 13-21

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Low frequency of BRAF mutations in endometrial and in cervical carcinomas.2006

    • Author(s)
      Moreno-Bueno G, Sanchez-Estevez C, Palacios J, Hardisson D, Shiozawa T
    • Journal Title

      Clin Cancer Res 12(12)

      Pages: 3865-3866

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Annual Research Report 2006 Final Research Report Summary
  • [Journal Article] Estrogen up-regulates mismatch repair activity in normal and malignant endometrial glandular cells.2006

    • Author(s)
      Miyamoto T, Shiozawa T, Kashima H, Feng YZ, Suzuki A, Kurai M, Nikaido T, Konishi I
    • Journal Title

      Endocrinology 147(10)

      Pages: 4863-4870

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Annual Research Report 2006 Final Research Report Summary
  • [Journal Article] Low frequency of BRAF mutations in endometrial and in cervical carcinomas.2006

    • Author(s)
      Moreno-Bueno G, Sanchez-Estevez C, Palacios J, Hardisson D, Shiozawa T
    • Journal Title

      Clin Cancer Res 12

      Pages: 3865-3866

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Review : Early endometrial carcinoma : Clinicopathology, hormonal aspects, molecular genetics, diagnosis, and treatment.2006

    • Author(s)
      Shiozawa T, Konishi I
    • Journal Title

      Int J Clin Oncol 11

      Pages: 13-21

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Estrogen up-regulates mismatch repair activity in normal and malignant endometrial glandular cells.2006

    • Author(s)
      Miyamoto T, Shiozawa T, Kashima H, Feng YZ, Suzuki A, Kurai M, Nikaido T, Konishi I
    • Journal Title

      Endocrinology 147

      Pages: 4863-4870

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Correlation between MRI and histopathologic findings in stage I cervical carcinomas : influence of stromal desmoplastic reaction.2006

    • Author(s)
      Itoh K, Shiozawa T, Ohira S, Shiohara S, Konishi I
    • Journal Title

      Int J Gynecol Cancer 16

      Pages: 610-614

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Cystic clear cell tumor of borderline malignancy of the ovary lacking fibromatous components : Report of two cases and a possible new histological subtype.2006

    • Author(s)
      Suzuki A, Shiozawa T, Mori A, Kimura K, Konishi I
    • Journal Title

      Gynecol Oncol 101

      Pages: 540-544

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Early endometrial carcinoma : clinicopathology, hormonal aspects, molecular genetics, diagnosis, and treatment.(Review)2006

    • Author(s)
      Shiozawa T, Ikuo K
    • Journal Title

      Int J Clin Oncol 11(1)

      Pages: 13-21

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Prenatal diagnosis of amniotic sheets by magnetic resonance imaging.2005

    • Author(s)
      Kato K, Shiozawa T, Ashida T, Unno N, Konishi I
    • Journal Title

      Am J Obstet Gynecol 193

      Pages: 881-884

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] BRAF mutation in endometrial carcinoma and hyperplasia : correlation with KRAS and p53 mutations and mismatch repair protein expression.2005

    • Author(s)
      Feng YZ, Shiozawa T, Miyamoto T, Kashima H, Kurai M, Suzuki A, Konishi I
    • Journal Title

      Clin Cancer Res 11

      Pages: 6133-6138

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary 2005 Annual Research Report
  • [Journal Article] Intratumoral heterogeneous expression of p53 correlates with p53 mutation, Ki-67,and cyclin A expression in endometrioid-type endometrial adenocarcinomas.2005

    • Author(s)
      Feng YZ, Shiozawa T, Horiuchi A, Shih HC, Miyamoto T, Kashima H, Suzuki A, Nikaido T, Konishi I
    • Journal Title

      Virchows Arch 447

      Pages: 816-822

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Leiomyoma of the ovary presenting with Meigs' syndrome.2005

    • Author(s)
      Kurai M, Shiozawa T, Noguchi H, Konishi I
    • Journal Title

      J Obstet Gynaecol Res 31

      Pages: 257-262

    • NAID

      10016451682

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Expression of cyclins, p53, and Ki-67 in cervical squamous cell carcinomas : overexpression of cyclin A is a poor prognostic factor in stage Ib and II disease.2005

    • Author(s)
      Shiohara S, Shiozawa T, Miyamoto T, Feng YZ, Kashima H, Kurai M, Suzuki A, Konishi I
    • Journal Title

      Virchows Arch 446

      Pages: 626-633

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Expression of Aurora kinases A and B in normal, hyperplastic, and malignant human endometrium : Aurora B as a predictor for poor prognosis in endometrial carcinoma.2005

    • Author(s)
      Kurai M, Shiozawa T, Shih HC, Miyamoto T, Feng YZ, Kashima H, Suzuki A, Konishi I
    • Journal Title

      Hum Pathol 36

      Pages: 1281-1288

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Intratumoral heterogeneous expression of p53 correlates with p53 mutation, Ki-67, and cyclin A expression in endometrioid-type endometrial adenocarcinomas.2005

    • Author(s)
      Feng YZ, Shiozawa T, Horiuchi A, Shih HC, Miyamoto T, Kashima H, Suzuki A, Nikaido T, Konishi I
    • Journal Title

      Virchows Arch 14

      Pages: 1-7

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Expression of cyclins, p53, and Ki-67 in cervical squamous cell carcinomas : overexpression of cyclin A is a poor prognostic factor in stage Ib and II disease.2005

    • Author(s)
      Shiohara S, Shiozawa T, Miyamoto T, Feng YZ, Kashima H, Kurai M, Suzuki A, Konishi I
    • Journal Title

      Virchows Archiv 446

      Pages: 626-633

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Prenatal diagnosis of amniotic sheets by magnetic resonance imaging.2005

    • Author(s)
      Kato K, Shiozawa T, Ashida T, Unno N, Konishi I
    • Journal Title

      Am J Obstet Gynecol 193(3 Pt 1)

      Pages: 881-884

    • Related Report
      2005 Annual Research Report

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Published: 2005-04-01   Modified: 2016-04-21  

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